U.S. patent application number 10/275242 was filed with the patent office on 2004-02-12 for benzosuberonylpiperdine compounds as analgesics.
Invention is credited to Barlocco, Daniela, Cignarella, Giorgio, Giardina, Giuseppe, Grugni, Mario, Ronzoni, Silvano.
Application Number | 20040029917 10/275242 |
Document ID | / |
Family ID | 9890994 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040029917 |
Kind Code |
A1 |
Barlocco, Daniela ; et
al. |
February 12, 2004 |
Benzosuberonylpiperdine compounds as analgesics
Abstract
Compounds of formula (I) or a derivative thereof, wherein; R is
C.sub.1-6allkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkoxy, hydroxy,
halo, C.sub.1-6alkenyl, C.sub.1-6allkynyl, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino,
hydroxyC.sub.1-6alkyl, C.sub.1-6akoxyC.sub.1-6al- kyl,
aminoC.sub.1-6allkyl, (C.sub.1-6allkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-6allkyl)aminoC.sub.1-6alkyl; R.sup.1 is hydrogen or R;
R.sup.2 is hydroxy, C.sub.1-6alkoxy, amino, C.sub.1-6alkylamino,
di(C.sub.1-6alkyl)amino; R.sup.3 is hydrogen or C.sub.1-6alkyl;
R.sup.4 and R.sup.5 are each independently selected from the list
consisting of perhaloC.sub.1-6alkyl, hydrogen, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, amino,
C.sub.1-6akylamino, di(C.sub.1-4alkyl)amino, hydroxyC.sub.1-6alkyl,
C.sub.1-6akoxyC.sub.1-6alkyl, aminoC.sub.1-6allkyl,
(C.sub.1-4alkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, aryl, and COX wherein X may
be hydroxy, C.sub.1-6alkoxy, C.sub.1-6alkyl, amino,
C.sub.1-6alkylamino, or di(C.sub.1-6allkyl)amino; with the proviso
that, when R.sup.3 is hydrogen, then R R.sup.4 and R.sup.5 are not
both hydrogen; and wherein any alkyl group or the alkyl moiety of
any group containing such a moiety may be substituted one or more
times by halo; are ligands of the ORL-1 receptor and are useful in
therapy. 1
Inventors: |
Barlocco, Daniela; (Milan,
IT) ; Cignarella, Giorgio; (Milan, IT) ;
Giardina, Giuseppe; (Milan, IT) ; Grugni, Mario;
(Milan, IT) ; Ronzoni, Silvano; (Milan,
IT) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION
CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
9890994 |
Appl. No.: |
10/275242 |
Filed: |
July 30, 2003 |
PCT Filed: |
May 1, 2001 |
PCT NO: |
PCT/EP01/04943 |
Current U.S.
Class: |
514/319 ;
546/205 |
Current CPC
Class: |
A61P 7/04 20180101; A61P
29/00 20180101; A61P 1/16 20180101; A61P 25/04 20180101; C07D
211/22 20130101; A61P 1/00 20180101; A61P 43/00 20180101; A61P 3/04
20180101; A61P 11/00 20180101; A61P 19/02 20180101; A61P 11/06
20180101; C07D 211/18 20130101; A61P 11/14 20180101; C07D 211/14
20130101; A61P 15/00 20180101; A61P 13/00 20180101; A61P 25/24
20180101; A61P 25/28 20180101; A61P 25/16 20180101; A61P 25/22
20180101; A61P 25/02 20180101; A61P 9/00 20180101; A61P 9/10
20180101; A61P 25/30 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/319 ;
546/205 |
International
Class: |
A61K 031/445; C07D
211/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2000 |
GB |
0010819.1 |
Claims
1. A compound of formula (I) 13or a derivative thereof, wherein; R
is C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkoxy, hydroxy,
halo, C.sub.1-6alkenyl, C.sub.1-6alkynyl, amino,
C.sub.1-6alylamino, di(C.sub.1-6alkyl)amino, hydroxyC.sub.1-6allyl,
C.sub.1-6alkoxyC.sub.1-6a- lkyl, aminoC.sub.1-6alkyl,
(C.sub.1-6alkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; R.sup.1 is hydrogen or R;
R.sup.2 is hydroxy, C.sub.1-6alkoxy, amino, C.sub.1-6alkylamino,
di(C.sub.1-6alkyl)amino; R.sup.3 is hydrogen or C.sub.1-6alkyl;
R.sup.4 and R.sup.5 are each independently selected from the list
consisting of perhaloC.sub.1-6alkyl, hydrogen, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino,
hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, (C.sub.1-6alkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, aryl, and COX wherein x may
be hydroxy, C.sub.1-6 alkoxy, C.sub.1-6alkyl, amino,
C.sub.1-6alkylamino, or di(C.sub.1-6alkyl)amino; with the proviso
that, when R.sup.3 is hydrogen, then R.sup.4 and R.sup.5 are not
both hydrogen; and wherein any alkyl group or the alkyl moiety of
any group containing such a moiety may be substituted one or more
times by halo.
2. A compound according to claim 1 wherein R is C.sub.1-6alkenyl,
C.sub.1-6alkyl, halo, or C.sub.1-6alkoxy.
3. A compound according to claim 1 or claim 2 wherein R is vinyl,
allyl, ethyl, methyl, fluoro, bromo, or methoxy.
4. A compound according to any one of claims 1 to 3 wherein R is
methyl, fluoro, or bromo.
5. A compound according to any one of claims 1 to 4 wherein R is
methyl.
6. A compound according to any one of claims 1 to 5 wherein R.sup.1
is hydrogen or methyl.
7. A compound according to any one of claims 1 to 6 wherein R.sup.1
is hydrogen or 4-methyl.
8. A compound according to any one of claims 1 to 7 wherein R.sup.2
is hydroxy.
9. A compound according to any one of claims 1 to 8 wherein R.sup.3
is hydrogen or methyl.
10. A compound according to any one of claims 1 to 9 wherein
R.sup.3 is hydrogen.
11. A compound according to any one of claims 1 to 10 wherein
R.sup.4 is hydroxyC.sub.1-6alkyl, halo, perhaloC.sub.1-6alkyl,
C.sub.1-6alkyl, or hydrogen.
12. A compound according to any one of claims 1 to 11 wherein
R.sup.4 is hydroxymethyl, fluoro, trifluoromethyl, chloro, methyl,
bromo, or hydrogen.
13. A compound according to any one of claims 1 to 12 wherein
R.sup.4 is 2-hydroxymethyl, 2-F, 2-CF.sub.3, 2-Cl, 2-Me, 3-Me,
2-Br, or hydrogen.
14. A compound according to any one of claims 1 to 13 wherein
R.sup.4 is 2-Cl, 2-F, 2-Me, or 2-Br.
15. A compound according to any one of claims 1 to 14 wherein
R.sup.4 is 2-Cl or 2-Me.
16. A compound according to any one of claims 1 to 15 wherein
R.sup.5 is C.sub.1-6alkyl, hydrogen, or halo.
17. A compound according to any one of claims 1 to 16 wherein
R.sup.5 is methyl, hydrogen, fluoro, or chloro.
18. A compound according to any one of claims 1 to 17 wherein
R.sup.5 is hydrogen, 6-Me, 3-F, 5-F, 6-F, or 6-Cl.
19. A compound according to any one of claims 1 to 18 wherein
R.sup.5 is hydrogen, 3-F, 6-Me, 6-F, or 6-Cl.
20. A compound according to any one of claims 1 to 19 wherein
R.sup.5 is 6Me, 6F, or 6-Cl.
21. A compound of formula (I) as defined in claim 1 selected from
Examples 1, 3, 4, 6, 8, 11, 14, 15, 19, 21, 24, 26, 22, 25, 16, and
18.
22. A compound of formula (I) as defined in claim 1 selected from
Examples 26, 22, 25, 16,and 18.
23. An enantiomer of a compound of formula (I) as defined in claim
1 or a derivative thereof.
24. A mixture of enantiomers of a compound of formula (I) as
defined in claim 1, or a derivative thereof, wherein one enantiomer
is present in a greater proportion than its antipode.
25. A process for the preparation of a compound of formula (I) as
defined in claim 1 wherein R.sup.2 is hydroxy and R.sup.3 is
hydrogen, which process comprises the reduction of a compound of
formula (II) 14wherein; R, R.sup.1, R.sup.4, and R.sup.5 are as
hereinbefore defined for formula (I); with a suitable reducing
agent such as a metal hydride or a borane-containing reducing agent
and thereafter, if required, carrying out one or more of the
following optional steps: (i) converting a compound of formula (I)
to another compound of formula (I); (ii) removing any necessary
protecting group; (iii) preparing an appropriate derivative of the
compound so formed.
26. A process for the preparation of a compound of formula (I) as
defined in claim 1 wherein R.sup.2 is hydroxy and R.sup.3 is
hydrogen, which process comprises reacting a compound of formula
(III) 15wherein; R and R.sup.1 are as hereinbefore defined for
formula (I) and P represents a protecting group; with a compound of
formula (V) 16wherein; R.sup.4 and R.sup.5 are as hereinbefore
defined for formula (I), under reductive amination conditions
followed by removal of the protecting group and thereafter, if
required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) to another compound of
formula (I); (ii) removing any necessary protecting group; (iii)
preparing an appropriate derivative of the compound so formed.
27. A process according to claim 26 wherein the protecting group,
P, is a silyl group.
28. A process for the preparation of a compound of formula (I) as
defined in claim 1 wherein R.sup.2 is hydroxy and R.sup.3 is
C.sub.1-6alkyl, which process comprises the oxidation of a compound
of formula (I) as defined in claim 1 wherein R.sup.2 is hydroxy and
R.sup.3 is hydrogen to give a compound of formula (I') 17wherein;
R, R.sup.1, R.sup.4, and R.sup.5 are as defined for formula (I) in
claim 1, followed by reaction of the compound of formula (I') with
a suitable organometallic compound and thereafter, if required,
carrying out one or more of the following optional steps: (i)
converting a compound of formula (I) to another compound of formula
(I); (ii) removing any necessary protecting group; (iii) preparing
an appropriate derivative of the compound so formed.
29. A process for the preparation of a compound of formula (I) as
defined in claim 1 wherein R.sup.2 is amino, C.sub.1-6alkylamino,
or di(C.sub.1-6alkyl)amino and R.sup.3 is hydrogen, which process
comprises the reduction of a compound of formula (VIII) 18wherein;
R, R.sup.1, R.sup.4, and R.sup.5 are as defined for formula (I) in
claim 1 and R.sup.6 and R.sup.7 are each independently hydrogen or
C.sub.1-6alkyl; and thereafter, if required, carrying out one or
more of the following optional steps: (i) converting a compound of
formula (I) to another compound of formula (I); (ii) removing any
necessary protecting group; (iii) preparing an appropriate
derivative of the compound so formed.
30. A compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, as an active
therapeutic substance.
31. A method of modulating the ORL-1 receptor activity in a human
or animal patient in need thereof, which method comprises
administering to the human or animal patient an effective amount of
a compound of formula (I) as defined in claim 1 or a
pharmaceutically acceptable derivative thereof.
32. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, for modulating the
ORL-1 receptor activity in a human or animal patient.
33. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, in the manufacture
of a medicament for modulating the ORL-1 receptor activity in a
human or animal patient.
34. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, as an analgesic for
the treatment of, for example, acute pain; chronic neuropathic or
inflammatory pain including post herpetic neuralgia; neuralgia;
diabetic neuropathy and post stroke pain; osteoarthritis/back pain;
painful pregnancy labour, and therapy of opioid tolerance and
dependence.
35. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, in the treatment or
prophylaxis of eating disorders such as anorexia and bulimia;
anxiety and stress conditions; immune system diseases;
cardiovascular system dysfunctions; memory loss; cognitive
disorders; motor impairment and neurodegeneration owing to
Alzheimer's disease; senile dementia; Parkinson's disease or other
neurodegenerative pathologies; stroke; epilepsy; altered diuresis
and sodium excretion; syndrome of inappropriate secretion of
antidiuretic hormone (SIADH); adult respiratory distress syndrome
(ARDS); congestive heart failure; cirrhosis with ascites; sexual
dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease.
36. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, in the treatment or
prophylaxis of cough; asthma; depression; drug abuse such as
alcohol abuse; dementias such as vascular dementia and AIDS
dementia complex; metabolic disorders such as obesity; arterial
blood pressure disorders; and for the control of water balance and
sodium excretion.
37. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof; for the manufacture
of a medicament as an analgesic for the treatment of, for example,
acute pain; chronic neuropathic or inflammatory pain including post
herpetic neuralgia; neuralgia; diabetic neuropathy and post stroke
pain; osteoarthritis/back pain; painful pregnancy labour; and
therapy of opioid tolerance and dependence.
38. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, for the manufacture
of a medicament for the treatment or prophylaxis of eating
disorders such as anorexia and bulimia; anxiety and stress
conditions; immune system diseases; cardiovascular system
dysfunctions; memory loss; cognitive disorders; motor impairment
and neurodegeneration owing to Allheimer's disease; senile
dementia; Parkinson's disease or other neurodegenerative
pathologies; stroke; epilepsy; altered diuresis and sodium
excretion; syndrome of inappropriate secretion of antidiuretic
hormone (SIADH); adult respiratory distress syndrome (ARDS);
congestive heart failure; cirrhosis with ascites; sexual
dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease.
39. Use of a compound of formula (I) as defined in claim 1, or a
pharmaceutically acceptable derivative thereof, for the manufacture
of a medicament for the treatment or prophylaxis of cough; asthma;
depression; drug abuse such as alcohol abuse; dementias such as
vascular dementia and AIDS dementia complex; metabolic disorders
such as obesity; arterial blood pressure disorders; and for the
control of water balance and sodium excretion.
40. A method of treatment of acute pain; chronic neuropathic or
inflammatory pain including post herpetic neuralgia; neuralgia;
diabetic neuropathy and post stroke pain; osteoarthritis/back pain;
painful pregnancy labour; and therapy of opioid tolerance and
dependence, which method comprises the administration of a compound
of formula (I) as defined in claim 1, or a pharmaceutically
acceptable derivative thereof, to the mammal in need thereof.
41. A method of treatment or prophylaxis of eating disorders such
as anorexia and bulimia; anxiety and stress conditions; immune
system diseases; cardiovascular system dysfunctions; memory loss;
cognitive disorders; motor impairment and neurodegeneration owing
to Alzheimer's disease; senile dementia; Parkinson's disease or
other neurodegenerative pathologies; stroke; epilepsy; altered
diuresis and sodium excretion; syndrome of inappropriate secretion
of antidiuretic hormone (SIADH); adult respiratory distress
syndrome (ARDS); congestive heart failure; cirrhosis with ascites;
sexual dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease, which method comprises the administration of a compound of
formula (I) as defined in claim 1, or a pharmaceutically acceptable
derivative thereof, to the mammal in need thereof.
42. A method of treatment or prophylaxis of cough; asthma;
depression; drug abuse such as alcohol abuse; dementias such as
vascular dementia and AIDS dementia complex; metabolic disorders
such as obesity; arterial blood pressure disorders; and for the
control of water balance and sodium excretion, which method
comprises the administration of a compound of formula (I) as
defined in claim 1, or a pharmaceutically acceptable derivative
thereof, to the mammal in need thereof.
43. A pharmaceutical composition comprising a compound of formula
(I) as defined in claim 1, or a pharmaceutically acceptable
derivative thereof, and a pharmaceutically acceptable carrier.
Description
[0001] The present invention relates to certain novel compounds, to
processes for preparing such compounds, to pharmaceutical
compositions containing such compounds, and to the use of such
compounds in medicine.
[0002] The ORL-1 receptor is found throughout the whole of the
neuraxis and is known to be involved in the taansmission of
pain.
[0003] Eur. J. Med. Chem. 1978; 13:533-547 (Eirin et al.) discloses
(.+-.)-3-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-diydronaphthalene
for use as a neuroleptic agent An. Real. Acad. Farm.
1989;55:461-469 (Santana et al.) discloses
(.+-.)-2-[(4-phenylpiperidin-1-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene as an antidopaminergic agent. U.S. Pat.
No. 4,022,791 (Pfizer Inc.) discloses certain
2-aminomethyl-3,4-dihydronaphth- alenes as analgesics. J. Med.
Chem. 1977;20(5):699-705 (Welch et al) discloses 5,8-disubstituted
1-tetralones as analgesics and tranquillisers. J. Med. Chem.
1978;21(3):257-263 (Welch et al) discloses certain
5,8-disubstituted 2-aminomethyl-3,4-dihydronaphthalenes as
analgesics and tranquillisers. International Application
Publication Number WO 98/36749 (Bristol-Myers Squibb) discloses
certain tetralone derivatives as antiarrhythmic agents. United
Kingdom Patent Application GB 2177085 (Imperial Chemical Industries
PLC) discloses certain benzocycloalkylmethylamines as fungicides.
WO 99/06397 (Abbott Laboratories) discloses certain piperidine
compounds useful as endothelin antagonists. WO 98/02432 (Takeda
Chemical Industries Ltd) discloses certain phenylpiperidino
compounds useful for the treatment of lower urinary tract
infections. WO 96/22977 (Suntory Limited) discloses certain
piperidinyl derivatives for treating symptoms of ischaemic diseases
and preventing cytotoxic calcium overload. WO 97/23458 (Cocensys
Inc.) discloses certain tetrahydronaphthyl and piperidine
derivatives as sub-type selective N-methyl-D-aspartame receptor
ligands. U.S. Pat. No. 5,436,255 Pfizer Inc.) discloses certain
3-piperidino-1-chromanof derivatives for blocking the NMDA receptor
site. WO 95/00131 (University of Virginia Commonwealth) discloses
certain amine derivatives as useful in the treatment of CNS
disorders. European Patent Application EP 0 745 598 (Adir et
Compagnie) discloses certain piperazine, piperidine, and
tetrahydropyridine compounds as ligands of the D.sub.4 dopamine
receptor. EP 0 742 207 (Eisai Co. Ltd.) discloses certain cyclic
amines as having acetyleholine esterase activity. U.S. Pat. No.
5,215,989 (Merck & Co. Inc.) discloses certain disubstituted
piperazine and imidazole derivatives useful as Class III
antiarrhythmic agents. WO 93/00313 (University of Virginia
Commonwealth) discloses certain amine derivatives as selective
sigma receptor binding agents. EP 0 479 601 (Ajinomoto K K)
discloses certain piperidine derivatives as antiarrhythmic agents.
Japanese Patent Application JP 2169 569 (Eisai K K) discloses
certain cyclic amine derivatives for the treatment or prophylaxis
of e.g. senile dementia, cerebral apoplexy, and cerebral
atherosclerosis. WO 00/06545 (Schering Corporation) discloses
certain piperidine and tetrahydropyridine derivatives as ORL-1
receptor ligands. WO 00/14067 (F. Hofmann-La Roche AG) discloses
certain piperidine derivatives as ligands for the OFQ (ORL-1)
receptor. WO 98/51687 (Fujisawa Pharmaceutical Co.) discloses
certain piperidino derivatives as promoters of growth hormone
release. WO 98/33758 (Takeda Chemical Industries) discloses certain
bicyclic quinone compounds. GB 2292558 (Merck and Co.) discloses
certain bicyclic compounds as fibrinogen receptor antagonists. WO
00/55137 (Axys Pharmaceuticals) discloses certain bicyclic
compounds as modulators of estrogen receptors. WO 00/32582 (Glaxo
Group Limited) discloses benzamide derivatives as APOB-100
secretion inhibitors. WO 00/27815 (SmithKline Beecham SpA)
discloses N-substituted azacycles as ORL-1 inhibitors. WO 00/12074
(Scios Inc.) discloses certain piperidines and piperazines as
inhibitors of P-38 alpha kinase. WO 98/38156 (Takeda Chemical
Industries Ltd.) discloses certain amino compounds and their use as
amyloid-beta production inhibitors. EP 846683 (F. Hoffmann La Roche
AG) discloses certain hydroxypiperidine derivatives.
[0004] It has now surprisingly been found that certain
benzosuberonylpiperidine derivatives are ligands of the ORL-1
receptor, and therefore may be useful as analgesics in humans or
animals for the treatment of, for example, acute pain; chronic
neuropathic or inflammatory pain including post herpetic neuralgia;
neuralgia; diabetic neuropathy and post stroke pain;
osteoarthritis/back pain; painful pregnancy labour; and therapy of
opioid tolerance and dependence.
[0005] These compounds may also therefore be useful in the
treatment or prophylaxis of eating disorders such as anorexia and
bulimia; anxiety and stress conditions; immune system diseases;
cardiovascular system dysfunctions; memory loss; cognitive
disorders; motor impairment and neurodegeneration owing to
Alzheimer's disease; senile dementia; Parkinson's disease or other
neurodegenerative pathologies; stroke; epilepsy; altered diuresis
and sodium excretion; syndrome of inappropriate secretion of
antidiuretic hormone (SIADH); adult respiratory distress syndrome
(ARDS); congestive heart failure;
[0006] wherein;
[0007] R is C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkoxy,
hydroxy, halo, C.sub.1-6alkenyl, C.sub.1-6alkynyl, amino,
C.sub.1-6alklylamino, di(C.sub.1-6alkyl)amino,
hydroxyC.sub.1-6alkyl, CI 6alkoxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, (C.sub.1-6alkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl;
[0008] R.sup.1 is hydrogen or R;
[0009] R.sup.2 is hydroxy, C.sub.1-6alkoxy, amino,
C.sub.1-6alkylamino, di(C.sub.1-6allyl)amino;
[0010] R.sup.3 is hydrogen or C.sub.1-6alkyl;
[0011] R.sup.4 and R.sup.5 are each independently selected from the
list consisting of perhaloC.sub.1-6alkyl, hydrogen, halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxy, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino,
hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxyC.sub.1-6a- lkyl,
aminoC.sub.1-6alkyl, (C.sub.1-6alkyl)aminoC.sub.1-6alkyl,
di(C.sub.1-6allkyl)aminoC.sub.1-6alkyl, aryl, and COX wherein X may
be hydroxy, C.sub.1-6 alkoxy, C.sub.1-6alkyl, amino,
C.sub.1-6alkylamino, or di(C.sub.1-6alkyl)amino;
[0012] with the proviso that, when R.sup.3 is hydrogen, then
R.sup.4 and R.sup.5 are not both hydrogen;
[0013] and wherein any alkyl group or the alkyl moiety of any group
containing such a moiety may be substituted one or more times by
halo.
[0014] Suitably, R is C.sub.1-6alkenyl, C.sub.1-6alkyl, halo, or
C.sub.1-6alkoxy.
[0015] Favourably, R is vinyl, allyl, ethyl, methyl, fluoro, bromo,
or methoxy.
[0016] Preferably, R is methyl, fluoro, or bromo.
[0017] More preferably, R is methyl.
[0018] Suitably, R.sup.1 is hydrogen or methyl.
[0019] Favourably, R.sup.1 is hydrogen or 4-methyl.
[0020] Suitably, R.sup.2 is hydroxy.
[0021] Favourably, R.sup.3 is hydrogen or methyl.
[0022] Preferably, R.sup.3 is hydrogen.
[0023] Suitably, R.sup.4 is hydroxyC.sub.1-6alkyl, halo,
perhaloC.sub.1-6alkyl, C.sub.1-6alkyl, or hydrogen.
[0024] Favourably, R.sup.4 is hydroxymethyl, fluoro,
trifluoromethyl, chloro, methyl, bromo, or hydrogen.
[0025] More favourably, R.sup.4 is 2-hydroxymethyl, 2-F,
2-CF.sub.3, 2-Cl, 2-Me, 3-Me, 2-Br, or hydrogen.
[0026] Preferably, R.sup.4 is 2-Cl, 2-F, 2-Me, or 2-Br.
[0027] More preferably, R.sup.4 is 2-Cl or 2-Me.
[0028] Suitably, R.sup.5 is C.sub.1-6alkyl, hydrogen, or halo.
[0029] Favourably, R.sup.5 is methyl, hydrogen, fluoro, or
chloro.
[0030] More favourably, R.sup.5 is hydrogen, 6-Me, 3-F, 5-F, 6-F,
or 6-Cl.
[0031] Preferably, R.sup.5 is hydrogen, 3-F, 6-Me, 6-F, or
6-Cl.
[0032] More preferably, R.sup.5 is 6-Me, 6-F, or 6-Cl.
[0033] Preferred compounds of formula (I) are Examples 1, 3, 4, 6,
8, 11, 14, 15, 19, 21, 24, 26, 22, 25, 16, and 18.
[0034] Compounds of formula (I) which are more preferred are
Examples 26, 22, 25, 16, and 18.
[0035] Suitable derivatives of the compounds of the invention are
pharmaceutically acceptable derivatives.
[0036] Suitable derivatives of the compounds of the invention
include salts and solvates.
[0037] Suitable pharmaceutically acceptable derivatives include
pharmaceutically acceptable salts and pharmaceutically acceptable
solvates.
[0038] Suitable pharmaceutically acceptable salts include metal
salts, such as for example aluminium, alkali metal salts such as
lithium, sodium or potassium, alkaline earth metal salts such as
calcium or magnesium and ammonium or substituted ammonium salts,
for example those with lower alkylamines such as triethylamine,
hydroxy alkylamines such as 2-hydroxyethylamine,
bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)ami- ne,
cycloalkylamines such as bicyclohexylamine, or with procaine,
dibenzylpiperidine, N-benzyl-.beta.-phenethylamine,
dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine,
N-methylglucamine or bases of the pyridine type such as pyridine,
collidine, quinine or quinoline.
[0039] Suitable pharmaceutically acceptable salts also includes
pharmaceutically acceptable acid addition salts, such as those
provided by pharmaceutically acceptable inorganic acids or organic
acids.
[0040] Suitable pharmaceutically acceptable acid addition salts
provided by pharmaceutically acceptable inorganic acids includes
the sulphate, nitrate, phosphate, borate, hydrochloride
hydrobromide and hydroiodide.
[0041] Suitable pharmaceutically acceptable acid addition salts
provided by pharmaceutically acceptable organic acids includes the
acetate, tartrate, maleate, fulmarate, malonate, citrate,
succinate, lactate, oxalate, benzoate, ascorbate,
methanesulphonate, .alpha.-ketoglutarate and
.alpha.-glycerophosphate, acetate, fumarate, salicylate, mandelate,
and methanesulphonate.
[0042] Suitable pharmaceutically acceptable solvates include
hydrates.
[0043] The compounds of formula (I) or their salts or solvates are
preferably in pharmaceutically acceptable or substantially pure
form. By pharmaceutically acceptable form is meant, initer alia, of
a pharmaceutically acceptable level of purity excluding normal
pharmaceutical additives such as diluents and carriers, and
including no material considered toxic at normal dosage levels.
[0044] A substantially pure form will generally contain at least
50% (excluding normal pharmaceutical additives), preferably 75%,
more preferably 90% and still more preferably 95% of the compound
of formula (I) or its salt or solvate.
[0045] One preferred pharmaceutically acceptable form is the
crystalline form, including such form in a pharmaceutical
composition. In the case of salts and solvates the additional ionic
and solvent moieties must also be non-toxic.
[0046] Unless otherwise stated, "alkyl" groups referred to herein,
including those forming part of other groups, include straight or
branched chain alkyl groups containing up to twelve, suitably up to
six carbon atoms. These alkyl groups may be optionally substituted
with up to five, suitably up to three, groups selected from the
list consisting of alkoxy, amino, carboxy and esters thereof,
cyano, hydroxy, and halogen.
[0047] Unless otherwise stated, "alkenyl" and "alkynyl" groups
referred to herein include straight and branched chain groups
containing from two to twelve, suitably from two to six, carbon
atoms. These alkenyl and alkynyl groups may be optionally
substituted with up to five, suitably up to three, groups including
those substituents described hereinbefore for the alkyl groups.
[0048] Unless otherwise stated, "cycloalkyl" groups referred to
herein include groups having between three and eight ring carbon
atoms. These cycloalkyl groups may be optionally substituted with
up to five, suitably up to three, groups including those
substituents hereinbefore described for the alkyl groups.
[0049] Unless otherwise stated, "aryl" includes phenyl, naphthyl,
and biphenyl groups, especially phenyl.
[0050] Suitable optional substituents for any aryl group include up
to five, suitably up to three, groups selected from the list
consisting of alkylnyl, amino, hydroxyalkyl, aminoalkyl, mono-and
di-alkylaminoalkyl, alkyl, alkylsulphonylamino, mono- and
di-alkylamino, mono- and di-alkylaminocarbonyl, arylcarbonyl,
aralkoxy, arylcarbonylamino, aminocarbonyl, aryl,
alkylaminocarbonyl, halo, alkyl, alkenyl, aralkyl, alkoxy,
alkoxyalkyl, hydroxy, nitro, amino, cyano, mono- and di-alkylamino,
acyl, acylamino, acyloxy, carboxy and esters thereof, carbamoyl,
aryloxy, cycloalkyl, and heterocyclyl.
[0051] Unless otherwise stated, "heterocyclyl" and "heterocyclic"
suitably include aromatic and non-aromatic, single and fused, rings
suitably containing up to four heteroatoms in each ring, each of
which is selected from oxygen, nitrogen and sulphur. Each ring
suitably has from 4 to 7, preferably 5 or 6, ring atoms. These
heterocyclyl and heterocyclic rings may be unsubstituted or
substituted by up to five substituents. A fused heterocyclic ring
system may include carbocyclic rings and need include only one
heterocyclic ring. Examples include pyridyl, indolinyl, quinolinyl,
indolyl, benzoxazolyl, benzothiazolyl, benzothiazolinonyl, and
benzoxazolinonyl.
[0052] Substituents for any heterocyclyl or heterocyclic group are
suitably selected from cyano, alkyl, aminocarbonyl, nitro, aryl,
arylcarbonyl, aryloxy, alkylcarbonyl, halogen, alkyl, aralkyl,
alkoxy, hydroxy, amino, carboxy and salts and esters thereof, and
aryl.
[0053] Unless otherwise stated, the terms "halogen" or "halo"
include iodo, bromo, chloro and fluoro; especially chloro, fluoro,
and bromo.
[0054] Certain of the compounds of formula (I) may contain chiral
atoms and/or multiple bonds, and hence may exist in one or more
stereoisomeric forms. The present invention encompasses all of the
isomeric forms of the compounds of formula (I) whether as
individual isomers or as mixtures of isomers, including geometric
isomers, tautomers, enantiomers, and racemic modifications.
[0055] It has been found that, where a compound of formula (I)
exhibits optical isomerism, one enantiomer possesses a greater
affinity for the ORL-1 receptor than its antipode.
[0056] Accordingly, the present invention also provides an
enantiomer of a compound of formula (I) or a derivative
thereof.
[0057] In a further aspect, the present invention provides a
mixture of enantiomers of a compound of formula (I), or a
derivative thereof, wherein one enantiomer is present in a greater
proportion than its antipode.
[0058] A further aspect of the invention provides a process for the
preparation of a compound of formula (I) wherein R.sup.2 is hydroxy
and R.sup.3 is hydrogen, and thereafter, if required, carrying out
one or more of the following optional steps:
[0059] (i) converting a compound of formula (I) to another compound
of formula (I);
[0060] (ii) removing any necessary protecting group;
[0061] (iii) preparing an appropriate derivative of the compound so
formed; which process comprises either;
[0062] Process A. the reduction of a compound of formula (II) 2
[0063] wherein;
[0064] R, R.sup.1, R.sup.4, and R.sup.5 are as hereinbefore defined
for formula (I) with a suitable reducing agent such as a metal
hydride or a borane-containing reducing agent, or;
[0065] Process B. reacting a compound of formula (III) 3
[0066] wherein;
[0067] R and R.sup.1 are as hereinbefore defined for formula (I)
and P represents a protecting group such as a silyl group, with a
compound of formula (I) 4
[0068] wherein;
[0069] R.sup.4 and R.sup.5 are as hereinbefore defined for formula
(I), under reductive amination conditions such as sodium
cyanoborohydride in methanol or acetonitrile (Lane, Synthesis, 135,
1975) and thereafter removing the protecting group using for
example mild acid hydrolysis or a fluorinated reagent such as
tetra-N-butylammonium fluoride to yield the compound of formula (I)
wherein R.sup.2 is hydroxy and R.sup.3 is hydrogen. A suitable
protecting group is a silyl group. Procedures for the protection
and deprotection of substituent groups are discussed in Greene and
Wuts Protective Groups in Organic Synthesis, III Edition, Wiley,
New York, (1999).
[0070] For a compound of formula (I) wherein R.sup.2 is hydroxy and
R.sup.3 is hydrogen, Process A is the preferred process.
[0071] For Process A in general, a solution of a compound of
formula (II) and a suitable reducing agent in a suitable dry
solvent is prepared under a suitable inert atmosphere at a suitable
initial temperature and is then stirred at a suitable reaction
temperature for a suitable period of time. A suitable reducing
agent is lithium aluminium hydride, lithium aluminium
hydride/aluminium trichloride, or diisobutylaluminium hydride. A
suitable solvent is tetrahydrofuran or diethyl ether. A suitable
inert atmosphere is an atmosphere of nitrogen. A suitable initial
temperature is in the range 0-4.degree. C. A suitable reaction
temperature is in the range 15.degree. C. to the reflux temperature
of the solvent. A suitable period of time is 2-18 hours. The
mixture is then quenched, basified, filtered if necessary, then, if
necessary, extracted into a suitable organic solvent. The solvent
is then removed and the crude product purified. Suitable quenching
media are water and saturated aqueous sodium potassium tartrate
tetrahydrate solution. A suitable base is aqueous sodium hydroxide
solution. A suitable organic extraction solvent is diethyl ether.
Conventional methods of cooling and heating such as ice/salt baths
and electric heating mantles may be employed. Conventional methods
of purification such as flash chromatography, trituration, and
crystallisation may be employed.
[0072] In a preferred aspect of Process A, a solution of aluminium
trichloride in dry diethyl ether is added dropwise at 0.degree. C.
to a suspension of lithium aluminium hydride in dry diethyl ether
under an atmosphere of nitrogen After stirring for ten minutes, a
solution of the compound of formula (II) in dry diethyl ether is
added dropwise, the reaction mixture allowed to warm to ambient
temperature, and stirred for four hours. After cooling to 0.degree.
C., the reaction is quenched by the sequential addition of water,
15% aqueous sodium hydroxide solution, and water. The aqueous phase
is extacted with diethyl ether, the organic phase is collected,
dried with, for example, magnesium sulphate and the solvent is
removed by evaporation. The crude product is purified by flash
chromatography followed by trituration.
[0073] A compound of formula (II) may be prepared by reaction of a
suitably activated compound of formula (V) 5
[0074] wherein;
[0075] R and R.sup.1 as hereinbefore defined for formula (I), with
a compound of formula (IV) as hereinbefore defined.
[0076] Compounds of formula (V) may suitably be activated prior to
reaction with the compound of formula (V) by formation of the
corresponding acyl halide, for example by reaction of the compound
of formula (II) with a halodehydroxylation agent such as oxalyl
chloride. Compounds of formula (V) may also be activated in situ
i.e. in the presence of the compound of formula (IV) by the use of
activating agents such as
dicyclohexylcarbodiimide/1-hydroxybenzotriazole,
N-ethyl-N-(3-dimethylaminopropyl)carbodiimide/1-hydroxybenzotriazole,
or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
[0077] In general, a compound of formula (II) may be prepared as
follows: To a solution of a compound of formula (V) in a suitable
dry solvent at a suitable initial temperature under a suitable
inert atmosphere is added a suitable halodehydroxylation agent The
solution is warmed to a suitable reaction temperature and for a
suitable period of time and the solvent removed under reduced
pressure. A suitable solvent is dichloromethane. A suitable initial
temperature is in the range of-2.degree. C. to 4.degree. C. A
suitable inert atmosphere is a nitrogen atmosphere. A suitable
halodehydroxylation agent is oxalyl chloride. A suitable reaction
temperature is in the range of 15.degree. C. to 25.degree. C. A
suitable period of time is 12 to 18 hours. Conventional methods of
cooling and heating such as ice/salt baths and electric heating
mantles may be employed. The crude acid halide is then reacted with
the compound of formula (IV) without further purification in the
following manner: At a suitable initial temperature and under a
suitable inert atmosphere, a solution of the crude acid halide in a
suitable dry solvent is added to a solution of the compound of
formula (IV), or a salt thereof, and a suitable hindered base in a
suitable dry solvent. A suitable initial temperature is in the
range of -2.degree. C. to 4.degree. C. A suitable inert atmosphere
is an atmosphere of nitrogen. A suitable solvent for the acid
halide, and the compound of formula (IV) and the hindered base is
dichloromethane. A hindered base is a base which does not act as a
competing nucleophile, such as triethylamine. The reaction mixture
is allowed to warm to a suitable reaction temperature for a
suitable period of time, water added, and the organic phase
separated, washed with a dilute aqueous solution of a suitable
mineral acid and dried with, for example, magnesium sulphate. A
suitable reaction temperature is in the range of 15.degree. C. to
25.degree. C. A suitable period of time is 12 to 18 hours. A
suitable mineral acid is hydrochloric acid. The crude compound of
formula (II) may be purified by conventional methods of
purification such as flash chromatography, crystalisation, and
trituration. Conventional methods of cooling and heating such as
ice/salt baths and electric heating mantles may be employed.
[0078] In a preferred aspect, the compound of formula (V) is
dissolved in dry dichloromethane and oxalyl chloride added dropwise
at 0.degree. C. under an atmosphere of nitrogen. The solution is
allowed to warm to ambient temperature for about 15 hours and the
solvent and excess oxalyl chloride removed under reduced pressure.
The resulting acid chloride is dissolved in dry dichloromethane,
added to a solution of the hydrochloride of the compound of formula
(IV) and triethylamine in dichloromethane at 0.degree. C. and
allowed to warm to ambient temperature for about 15 hours. Water is
then added, the organic phase separated, washed with 1M aqueous
hydrochloric acid and dried with, for example, magnesium sulphate.
The solvent is removed under reduced pressure and the crude
compound of formula (II) purified by flash chromatography.
[0079] Compounds of formula (V) may be prepared as described in
Bowman, Tetrahedron, 48, 4027, (1992), or Hasegawa, Tetrahedron
Lett., 39, 4059, (1998), or may be prepared by transforming the
hydroxy group of an alcohol of formula (XII) into a suitable
leaving group such as methanesulphonate, p-toluenesulphonate or
bromide, and reacting said compound with diethyl malonate in
presence of a base such as sodium ethoxide to obtain a compound of
formula (XOI). The compound of formula (XI) is then alkylated with
t-butyl bromoacetate in the presence of a base such as sodium
hydride to yield a compound of formula (XIV). The t-butyl ester is
then selectively hydrolysed with, for example trifluoroacetic acid
to yield the carboxylic acid (XV), which is thereafter converted to
the corresponding acyl chloride, cyclised under Friedel-Crafts
conditions and subsequently hydrolysed and decarboxylated using
conventional methods. See Scheme 1. 6
[0080] wherein R and R.sup.1 are as hereinbefore defined for
formula (I).
[0081] Compounds of formula (IV) may be prepared as described in
Elliott, Bioorg. Med. Chem. Lett., 8, 1851, (1998) or may be
prepared by reacting an aromatic aldehyde of formula (XVI) with
ethyl acetoacetate in presence of a catalytic amount of an organic
base such as piperidine, to give compound (XVII), which is
thereafter hydrolysed in basic conditions for example in the
presence of aqueous sodium hydroxide solution, to yield the
carboxylic acid (XVIII), which is then transformed into the imide
(XIX) by conversion to its ammonium salt and subsequent pyrolysis,
and finally reducing said imide using a suitable metal hydride or a
borane-based reagent. See Scheme 2. 7
[0082] wherein R.sup.4 and R.sup.5 are as hereinbefore defined for
formula (I), or by reacting a carboxylic compound of formula I,
wherein P is a suitable protecting group such as benzyl, with an
organometallic compound of formula (KU), wherein M represents a
metal such as Li or Mg, for example arylithium derivatives or
Grignard reagents, obtaining an alcohol of formula (XII),
dehydrating said alcohol to a compound of formula (XXII) in acidic
conditions (e.g. conc. HCl or AcOH/H.sub.2SO.sub.4) and finally
reducing and deprotecting the compound of formula (XII) via
hydrogenation over a suitable catalyst (e.g. Pd on carbon or
PtO.sub.2) or via dissolving metal reduction (e.g. Li or Na in
liquid ammonia). See Scheme 3. 8
[0083] wherein R.sup.4 and R.sup.5 are as hereinbefore defined for
formula (I).
[0084] Compounds of formula (W are known, commercially available
compounds or may be prepared according to procedures described in
standard reference texts of synthetic methodology such as J. March,
Advanced Organic Chemistry, 3rd Edition (1985), Wiley
Interscience.
[0085] Compounds of formula (XVI) are known, commercially available
compounds, or may be prepared according to procedures described in
standard reference texts of synthetic methodology such as J. March,
Advanced Organic Chemistry, 3rd Edition (1985), Wiley
Interscience.
[0086] Compounds of formula (XX) are known, commercially available
compounds, or may be prepared according to procedures described in
standard reference texts of synthetic methodology such as J. March,
Advanced Organic Chemistry, 3rd Edition (1985), Wiley
Interscience.
[0087] Compounds of formula (X) are known and may be prepared
according to procedures described in standard reference texts of
synthetic methodology such as J. March, Advanced Organic Chemistry,
3rd Edition (1985), Wiley Interscience.
[0088] Compounds of formula (III) may be prepared from compounds of
formula (VI) 9
[0089] wherein;
[0090] R and R.sup.1 are as hereinbefore defined for formula (I) by
protection of the hydroxy group with a suitable protecting group
such as a silyl group, followed by reduction of the ester moiety to
an aldehyde group using a suitable reducing agent such as
diisobutylaluminium hydride (Winterfeldt, Synthesis, 617,
(1975)).
[0091] Compounds of formula (VI) may be prepared from compounds of
formula (VII) 10
[0092] wherein;
[0093] R and R.sup.1 are as hereinbefore defined for formula (I) by
conventional reduction procedures for example-using a suitable
reducing agent such as sodium borohydride.
[0094] Compounds of formula (VII) may be prepared from compounds of
formula (V) by conventional esterification procedures for example
those described in standard reference texts of synthetic
methodology such as J. March, Advanced Organic Chemistry, 3rd
Edition (1985), Wiley Interscience.
[0095] In a further aspect, there is provided a process for the
preparation of a compound of formula (I) wherein R.sup.2 is hydroxy
and R.sup.3 is C.sub.1-6alkyl, which process comprises the
oxidation of a compound of formula (a) wherein R.sup.2 is hydroxy
and R.sup.3 is hydrogen using a suitable oxidising agent such as
MnO.sub.2, PDC, or DMSO/oxalyl chloride (Swem J. Org. Chem. 43 2480
(1978)) to give a compound of formula (I') 11
[0096] wherein;
[0097] R, R.sup.1, R.sup.4, and R.sup.5 are as hereinbefore defined
for formula (I), followed by reaction of the compound of formula
(I') with a suitable organometallic compound such as an alkylmetal
compound for example an alkyllithium compound, or a Grignard
reagent such as an alkyl Grignard reagent, and thereafter, if
required, carrying out one or more of the following optional
steps:
[0098] (i) converting a compound of formula (I) to another compound
of formula (I);
[0099] (ii) removing any necessary protecting group;
[0100] (iii) preparing an appropriate derivative of the compound so
formed.
[0101] In general, a solution of the compound of formula (I') in a
suitable dry solvent at a suitable initial temperature under a
suitable inert atmosphere is added to a solution of the
organometallic reagent in a suitable dry solvent. The reaction
mixture is stirred at the initial temperature for a suitable
initial time period, then warmed to a suitable second temperature
and stirred for a suitable second time period. The mixture is then
cooled to the initial temperature and quenched with a suitable
quenching medium A suitable solvent for the compound of formula
(I') and the organometallic reagent is diethyl ether. A suitable
initial temperature is in the range-2.degree. C. to 4.degree. C. A
suitable inert atmosphere is an atmosphere of nitrogen. A suitable
initial time period is 30 minutes to 2 hours. A suitable second
temperature is 15.degree. C. to 25.degree. C. A suitable second
time period is 30 minutes to 2 hours. A suitable quenching medium
is saturated aqueous ammonium chloride solution. The aqueous phase
is extracted with a suitable organic solvent such as diethyl ether,
the organic extract isolated, dried with for example magnesium
sulphate, and the solvent removed under reduced pressure. The crude
product is then purified. Conventional means of heating and cooling
for example ice/salt baths and electric-heating mantles may be
employed. Conventional methods of purification such as flash
chromatography, crystallisation, and trituration may be
employed.
[0102] In a preferred aspect, a solution of the compound of formula
(I') in dry diethyl ether is added at 0.degree. C. and under an
atmosphere of nitrogen to a solution of CI alkyl magnesium iodide
in dry diethyl ether. The mixture is stirred at 0.degree. C. for
one hour, allowed to warm to ambient temperature and stirred for a
further one hour. The mixture is then cooled to 0.degree. C. and
quenched with saturate aqueous ammonium chloride solution. The
aqueous phase was extracted with diethyl ether, the organic layer
separated, dried, and the solvent removed under reduced pressure.
The crude compound of formula (I) wherein R.sup.2 is hydroxy and
R.sup.3 is C.sub.1-6alkyl is then purified by flash
chromatography.
[0103] In an additional aspect, there is provided a process for the
preparation of a compound of formula (I) wherein R.sup.2 is amino,
C.sub.1-6alkylamino, or di(C.sub.1-6alkyl)amino and R.sup.3 is
hydrogen, which process comprises the reduction of a compound of
formula (VIII) 12
[0104] wherein;
[0105] R, R.sup.1, R.sup.4, and R.sup.5 are as hereinbefore defined
for formula (I) and R.sup.6 and R.sup.7 are each independently
hydrogen or C.sub.1-6alkyl, using a suitable reducing agent such as
a metal hydride or a borane-based reagent as hereinbefore described
in Process A, and thereafter, if required, carrying out one or more
of the following optional steps:
[0106] (i) converting a compound of formula (I) to another compound
of formula (I);
[0107] (ii) removing any necessary protecting group;
[0108] (iii) preparing an appropriate derivative of the compound so
formed.
[0109] Compounds of formula (VII) may be prepared from compounds of
formula (II) as hereinbefore defined by reaction with a compound of
formula (IX)
HNR.sup.6R.sup.7 (IX)
[0110] wherein;
[0111] R.sup.6 and R.sup.7 are each independently hydrogen or
C.sub.1-6alkyl, under reductive amination conditions as
hereinbefore described in Process B.
[0112] Compounds of formula (IX) are known, commercially available
compounds or may be prepared according to procedures described in
standard reference texts of synthetic methodology such as J. March,
Advanced Organic Chemistry, 3rd Edition (1985), Wiley
Interscience.
[0113] The above mentioned conversion of a compound of formula (I)
into another compound of formula (I) includes any conversion which
may be effected using conventional procedures, but in particular
the said conversions include:
[0114] (a). converting one group R.sup.2 into another group
R.sup.2.
[0115] The above mentioned conversion (a) may be carried out using
any appropriate method under conditions determined by the
particular groups chosen.
[0116] Suitable conversions of one group R.sup.2 into another group
R.sup.2, as in conversion (a), include:
[0117] (i). converting a group R.sup.2 which represents hydroxy
into a group R.sup.2 which represents alkoxy; such a conversion may
be carried out using a conventional alkylation procedure, for
example treating an appropriately protected compound of formula (I)
with a strong base such as sodium hydride and alkylating the
resultant alkoxide anion with a suitable alkylating agent such as
an alkyl halide, and;
[0118] (ii). converting a group R.sup.2 which represents hydroxy
into a group R.sup.2 which represents amino, alkylamino, or
dialkylamino; such a conversion may be carried out using a
conventional dehydroxyamination procedure, for example treating an
appropriately protected compound of formula (I) wherein R.sup.2 is
hydroxy with an activating agent such as a methanesulphonyl halide
or a p-toluenesulphonyl halide to transform the hydroxy group
R.sup.2 into the corresponding methanesulphonate or
p-toluenesulphonate respectively and thereafter reacting the
activated compound with an amine of formula (IX) as hereinbefore
defined in the presence of a hindered base such as
triethylamine.
[0119] As has previously been mentioned, compounds of formula (I)
are ligands of the ORL-1 receptor.
[0120] Accordingly, there is provided a compound of formula (I), or
a pharmaceutically acceptable derivative thereof, as an active
therapeutic substance.
[0121] According to another aspect of the present invention there
is provided a method of modulating the ORL-1 receptor activity in a
human or animal patient in need thereof, which method comprises
administering to the human or animal patient an effective amount of
a compound of formula (I) or a pharmaceutically acceptable
derivative thereof.
[0122] In a further aspect of the present invention there is
provided the use of a compound of formula (I), or a
pharmaceutically acceptable derivative thereof, for modulating the
ORL-1 receptor activity in a human or animal patient.
[0123] In yet another aspect of the present invention there is
provided the use of a compound of formula (I), or a
pharmaceutically acceptable derivative thereof, in the manufacture
of a medicament for modulating the ORL-1 receptor activity in a
human or animal patient.
[0124] Said compounds of formula (I) may be agonists or antagonists
of the ORL-1 receptor.
[0125] Accordingly, the present invention provides the use of a
compound of formula (I), or a pharmaceutically acceptable
derivative thereof, as an analgesic for the treatment of, for
example, acute pain; chronic neuropathic or inflammatory pain
including post herpetic neuralgia; neuralgia; diabetic neuropathy
and post stroke pain; osteoarthritis/back pain; painful pregnancy
labour, and therapy of opioid tolerance and dependence.
[0126] Accordingly, the present invention further provides the use
of a compound of formula (I), or a pharmaceutically acceptable
derivative thereof, in the treatment or prophylaxis of eating
disorders such as anorexia and bulimia; anxiety and stress
conditions; immune system diseases; cardiovascular system
dysfunctions; memory loss; cognitive disorders; motor impairment
and neurodegeneration owing to Alzheimer's disease; senile
dementia; Parkinson's disease or other neurodegenerative
pathologies; stroke; epilepsy; altered diuresis and sodium
excretion; syndrome of inappropriate secretion of antidiuretic
hormone (SLADH); adult respiratory distress syndrome (ARDS);
congestive heart failure; cirrhosis with ascites; sexual
dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease.
[0127] Accordingly, the present invention also provides the use of
a compound of formula (I), or a pharmaceutically acceptable
derivative thereof, in the treatment or prophylaxis of cough;
asthma; depression; drug abuse such as alcohol abuse; dementias
such as vascular dementia and AIDS dementia complex; metabolic
disorders such as obesity; arterial blood pressure disorders; and
for the control of water balance and sodium excretion.
[0128] In a further aspect, the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable
derivative thereof, for the manufacture of a medicament as an
analgesic for the treatment of, for example, acute pain; chronic
neuropathic or inflammatory pain including post herpetic neuralgia;
neuralgia; diabetic neuropathy and post stroke pain;
osteoarthritis/back pain; painful pregnancy labour; and therapy of
opioid tolerance and dependence.
[0129] In an additional aspect, the present invention provides the
use of a compound of formula (I), or a pharmaceutically acceptable
derivative thereof, for the manufacture of a medicament for the
treatment or prophylaxis of eating disorders such as anorexia and
bulimia; anxiety and stress conditions; immune system diseases;
cardiovascular system dysfunctions; memory loss; cognitive
disorders; motor impairment and neurodegeneration owing to
Alzheimer's disease; senile dementia; Parkinson's disease or other
neurodegenerative pathologies; stroke; epilepsy; altered diuresis
and sodium excretion; syndrome of inappropriate secretion of
antidiuretic hormone (SIADM); adult respiratory distress syndrome
(ARDS); congestive heart failure; cirrhosis with ascites; sexual
dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease.
[0130] In yet a further aspect, the present invention provides the
use of a compound of formula (I), or a pharmaceutically acceptable
derivative thereof, for the manufacture of a medicament for the
treatment or prophylaxis of cough; asthma; depression; drug abuse
such as alcohol abuse; dementias such as vascular dementia and AIDS
dementia complex; metabolic disorders such as obesity; arterial
blood pressure disorders; and for the control of water balance and
sodium excretion.
[0131] Accordingly, in a further aspect, there is provided a method
of treatment of acute pain; chronic neuropathic or inflammatory
pain including post herpetic neuralgia; neuralgia; diabetic
neuropathy and post stroke pain; osteoarthritis back pain; painful
pregnancy labour, and therapy of opioid tolerance and dependence,
which method comprises the administration of a compound of formula
(I), or a pharmaceutically acceptable derivative thereof, to the
mammal in need thereof.
[0132] In a further aspect, there is provided a method of treatment
or prophylaxis of eating disorders such as anorexia and bulimia;
anxiety and stress conditions; immune system diseases;
cardiovascular system dysfunctions; memory loss; cognitive
disorders; motor impairment and neurodegeneration owing to
Alzheimer's disease; senile dementia; Parkinson's disease or other
neurodegenerative pathologies; stroke; epilepsy; altered diuresis
and sodium excretion; syndrome of inappropriate secretion of
antidiuretic hormone (SIADH); adult respiratory distress syndrome
(ARDS); congestive heart failure; cirrhosis with ascites; sexual
dysfunctions including impotence and frigidity; and altered
pulmonary function, including chronic obstructive pulmonary
disease, which method comprises the administration of a compound of
formula (I), or a pharmaceutically acceptable derivative thereof,
to the mammal in need thereof.
[0133] In yet a further aspect, there is provided a method of
treatment or prophylaxis of cough; asthma; depression; drug abuse
such as alcohol abuse; dementias such as vascular dementia and AIDS
dementia complex; metabolic disorders such as obesity; arterial
blood pressure disorders; and for the control of water balance and
sodium excretion, which method comprises the administration of a
compound of formula (I), or a pharmaceutically acceptable
derivative thereof, to the mammal in need thereof.
[0134] Administration of a compound in accordance with the
invention may be by way of oral, sublingual, transdermal or
parenteral administration.
[0135] An effective amount of the compound of the invention will
depend on factors such, for example, as the nature and severity of
the disorder(s) being treated and on the weight of the mammal.
However, a unit does will normally contain 0.1 to 50 mg, for
example 0.5 to 10 mg, of the compound. Unit doses will normally be
administered once or more than once a day, for example 2, 3, or 4
times a day, more usually 1 to 3 times a day, such that the total
daily dose is normally in the range, for a 70 kg adult of 0.1 to 50
mg, for example 0. 1 to 5 mg, that is in the range of approximately
0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
[0136] For oral or parenteral administration, it is greatly
preferred that the compound is administered in the form of a unit
dose composition, such as a unit dose oral or parenteral
composition.
[0137] Accordingly, in yet another aspect of the present invention
there is also provided a pharmaceutical composition comprising a
compound of formula (I), or a pharmaceutically acceptable
derivative thereof, and a pharmaceutically acceptable carrier.
[0138] Such compositions are prepared by admixture and are suitably
adapted for oral or parenteral administration, and as such may be
in the form of tablets, capsules, oral preparations, powders,
granules, lozenges, reconstitutable powders, injectable and liquid
infusible solutions or suspensions or suppositories.
[0139] Tablets and capsules for oral administration are usually
presented in a unit dose, and contain conventional excipients such
as binding agents, fillers, diluents, tabletting agents,
lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets may be coated according to well known methods
in the art.
[0140] Suitable fillers include cellulose, mannitol, lactose and
other similar agents.
[0141] Suitable disintegrants include starch, polyvinylpyrrolidone
and starch derivatives such as sodium starch glycolate.
[0142] Suitable lubricants include, for example, magnesium
stearate.
[0143] Suitable pharmaceutically acceptable wetting agents include
sodium lauryl sulphate.
[0144] These solid oral compositions may be prepared by
conventional methods of blending, filling or tabletting. Repeated
blending operations may be used to distribute the active agent
throughout those compositions employing large quantities of
fillers. Such operations are conventional in the art.
[0145] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups, or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example sorbitol, syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate
gel or hydrogenated edible fats, emulsifying agents, for example
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles
(which may include edible oils), for example, almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired
conventional flavouring or colouring agents.
[0146] Oral formulations also include conventional sustained
release formulations, such as tablets or granules having an enteric
coating.
[0147] For parenteral administration, fluid unit dose forms may be
prepared containing the compound and a sterile vehicle. The
compound, depending on the vehicle and the concentration, can be
either suspended or dissolved. Parenteral solutions are normally
prepared by dissolving the compound in a vehicle and filter
sterilising before filling into a suitable vial or ampoule and
sealing. Advantageously, adjuvants such as a local anaesthetic,
preservatives and buffering agents are also-dissolved in the
vehicle. To enhance the stability, the composition may be frozen
after filling into the vial and the water removed under vacuum.
[0148] Parenteral suspensions are prepared in substantially the
same manner except that the compound may be suspended in the
vehicle instead of being dissolved and sterilised by exposure to
ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent may be included in
the composition to facilitate uniform distribution of the compound
of the invention.
[0149] As is common practice, the compositions will usually be
accompanied by written or printed directions for use in the
treatment concerned.
[0150] Preparation 1
[0151] 2-Methylphenethyl alcohol methanesulphonate
[0152] 10 g (0.0734 mol) of 2-methylphenethyl alcohol were
dissolved in 200 mL of dry CH.sub.2Cl.sub.2 under a nitrogen
atmosphere; the solution was cooled to 5.degree. C., 16.4 mL
(0.1175 mol) of triethylamine were added, followed by a solution of
9.1 mL (0.1175 mol) of methanesulphonyl chloride in 100 mL of dry
CH.sub.2Cl.sub.2, keeping the temperature below 15.degree. C. The
reaction mixture was allowed to warm to room temperate in 2 h, then
250 mL of water were added, the organic phase was collected and the
solvent was removed in vacuo. The resulting oil was taken up in
Et.sub.2O, the organic phase was washed with 1N HCl and with
saturated NaHCO.sub.3 solution, then it was dried and the solvent
was removed in vacuo, yielding 14.5 g of the title product which
was used without further purification.
[0153] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0154] Preparation 2
[0155] 2-(2-o-Tolyl-ethyl)-malonic Acid Diethyl Ester
[0156] 33.9 mL (0.223 mol) of diethyl malonate were added, under a
nitrogen atmosphere and at room temperature, to a solution of
sodium ethoxide (prepared in situ by dissolving 2.6 g (0.0151 mol)
of Na in 80 mL of absolute EtOH). After 30 min, 14.5 g (0.0677 mol)
of 2-methylphenethyl alcohol methanesulphonate dissolved in 40 mL
of abs. EtOH were added dropwise and the resulting solution was
heated to reflux for 3 h. EtOH was removed in vacuo, the residue
was taken up in water and extracted with Et.sub.2O. The organic
phase was washed successively with 10% HCl and brine, dried and the
solvent was removed in vacuo. The excess diethyl malonate was
removed by distillation under reduced pressure. The resulting oil
(15.6 g) was used without further purification.
[0157] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0158] Preparation 3
[0159] 3,3-Bis-ethoxycarbonyl-5-o-tolyl-pentanoic acid tert-butyl
Ester
[0160] A solution of 7.7 g (0.0277 mol) of
22-o-tolyl-ethyl)-malonic acid diethyl ester in 70 ml of dry THF
was added dropwise, under a nitrogen atmosphere at room
temperature, to a suspension of 1.4 g (0.036 mol) of NaH (60%
dispersion in mineral oil) in 160 mL of dry TH. The reaction
mixture was stirred for 30 min, ten 5.3 mL (0.036 mol) of t-butyl
bromoacetate were added dropwise. After 3 h the reaction mixture
was quenched with water (at 0.degree. C.) and extracted with
Et.sub.2O. The organic phase was dried, the solvent was removed in
vacuo and the residue was purified by flash chromatography, eluting
with a mixture Hexane/Et.sub.2O 8:2, yielding 9.3 g of the title
compound.
[0161] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0162] Preparation 4
[0163] 3,3-Bis-ethoxycarbonyl-S-o-tolyl-pentanoic Acid
[0164] 18.7 g (0.0476 mol) of
3,3-bis-ethoxycarbonyl-S-o-tolyl-pentanoic acid tert-butyl ester
were dissolved in 40 mL of trifluoroacetic acid and stirred 1 h at
room temperature. Trifluoroacetic acid was removed in vacuo, the
residue was taken up in water and extracted with Et.sub.2O. The
organic phase was dried and the solvent was removed in vacuo,
yielding 16.8 g of the title compound which was used without
further purification
[0165] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0166] Preparation 5.
[0167]
(.+-.)-1-Methyl5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7carbo-
xylic Acid
[0168] 16.8 g (0.0499 mol) of
3,3-bis-ethoxycarbonyl-5-o-tolyl-pentanoic acid were dissolved in
120 mL of CH.sub.2Cl.sub.2 under a nitrogen atmosphere. The
solution was cooled to 5.degree. C. and 19 mL (0.1498 mol) of
oxalyl chloride were added dropwise. After 3 h the volatiles were
removed in vacuo, the resulting oil was dissolved in 200 mL of
CH.sub.2Cl.sub.2 and this solution was added dropwise, at 0.degree.
C. and under inert atmosphere, to a suspension of 26.6 g (0.1996
mol) of AlC.sub.3 in 300 mL of CH.sub.2Cl.sub.2. The resulting
suspension was vigorously stirred overnight, during which time it
was allowed to warm to room temperature. Water was added, followed
by 1N HCl up to pH 1. The layers were separated, the organic phase
was dried and the solvent was removed in vacuo. The resulting crude
product was taken up in dioxane (60 mL) and 6N HCl (200 mL) and
heated to reflux for 6 h. After cooling, water was added and the
reaction mixture was extracted with Et.sub.2O. The organic phase
was dried, the solvent was removed in vacuo and the resulting crude
product was purified by flash chromatography eluting with
Et.sub.2O, yielding 5.9 g of compound which was triturated in
(i-Pr).sub.2O, filtered and dried, yielding 4.33 g of the title
product.
[0169] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0170] The following compounds were obtained according to
procedures described in Preparations 1-5:
[0171]
(.+-.)-1,4-Dimethyl-S-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-
-carboxylic acid;
[0172]
(.+-.)-1-Fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-car-
boxylic acid, and;
[0173]
(.+-.)-1-Bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carb-
oxylic acid.
[0174] IR, .sup.1H nmr spectra and mass spectra for all the above
compounds were consistent with the assigned structures.
[0175] Preparation 6
[0176]
(.+-.)-1-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-ca-
rboxylic Acid
[0177] A suspension of 0.7 g of
(.+-.)-1-methoxy-5-oxo-6,7,8,9-tetrahydro--
5H-benzocycloheptene-7-carboxylic acid ethyl ester (prepared as
described in Bowman, Tetrahedron, 48, 4027, 1992) in 2 mL of 2N
NaOH was refluxed for 2 h, then cooled and extracted with
Et.sub.2O. The aqueous layer was brought to acidic pH with 10% HCl,
the precipitate formed was redissolved in Et.sub.2O and the organic
phase was washed with water and dried. The solvent was removed in
vacuo and the resulting residue was purified by flash
chromatography, eluting with a mixture CH.sub.2Cl.sub.2/MeOH 9:1
respectively, yielding 0.41 g of the title compound.
[0178] IR and .sup.1H nmr spectra were consistent with the assigned
structure.
[0179] Preparation 7
[0180]
2-(2,6-Dichloro-phenyl)-4-hydroxy-4-methyl-6-oxo-cyclohexane-13-dic-
arboxylic Acid Diethyl Ester
[0181] 20 g (114.3 mmol) of 2,6-dichlorobenzaldehyde and 29 mL
(228.6 mmol) of ethyl acetoacetate were dissolved in 40 mL of 96%
EtOH; 2 mL of piperidine were added dropwise and the resulting
solution was stirred overnight at room temperature. EtOH was
removed in vacuo and the resulting residue was crystallised from
Et.sub.2O, obtaining 25.8 g of the title product
[0182] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0183] Preparation 8
[0184] 3-(2,6-Dichloro-phenyl)-pentanedioic Acid
[0185] 25.8 g (61.8 mmol) of
2-(2,6-chloro-phenyl).sub.4-hydroxymethyl-6-o-
xo-cyclohexane-1,3-dicarboxylic acid diethyl ester were dissolved
in 200 mL of 96% EtOH, 150 mL of 35% NaOH solution and 60 mL of
H.sub.2O; the resulting solution was heated to reflux for 3 h, then
the solvent was removed in vacuo and the resulting aqueous solution
was carefully acidified at 0.degree. C. with conc. HCl and
extracted with AcOEt. The organic solution was dried and the
solvent was removed in vacuo. The resulting crude solid was
triturated with Et.sub.2O, filtered and dried, yielding 14.8 g of
the title compound.
[0186] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0187] Preparation 9
[0188] 4-(2,6-Dichloro-phenyl)-piperidine-2,6-dione
[0189] 14.5 g (52 mmol) of 3-(2,6-dichloro-phenyl)-pentanedioic
acid were dissolved in 140 mL of conc. NH.sub.4OH solution. All the
volatiles were removed in vacuo and the resulting solid was heated
to 190.degree. C. for 6 h. The crude reaction mixture was taken up
in CH.sub.2Cl.sub.2, the organic phase was washed with 0.1 M
Na.sub.2CO.sub.3 solution, dried and evaporated to dryness. The
resulting crude solid was triturate with Et.sub.2O, filtered and
dried, yielding 9.37 g of the title compound.
[0190] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0191] Preparation 10
[0192] 4-(2,6-Dichloro-phenyl)piperidine hydrochloride
[0193] 9.0 g (34.9 mmol) of
4-(2,6-dichloro-phenyl)-piperidine-2,6-dione were dissolved in 150
mL of dry THF under a nitrogen atmosphere. The resulting solution
was cooled to 0.degree. C. and 35 mL (ca 350 mmol) of
borane-methylsulphide complex dissolved in 100 mL of dry THF were
added dropwise. The reaction mixture was allowed to warm to room
temperature, heated to reflux for 3 h, then cooled to -5.degree. C.
and quenched by careful addition of 150 mL of 10% HCl solution. The
reaction mixture was subsequently heated to reflux for 3 h, then,
after cooling, the volatiles were removed in vacuo. The residue was
taken up in water, basified with 2 N NaOH solution and extracted
with AcOEt The organic phase was dried and the solvent was removed
in vacuo. The resulting oil was taken up in CH.sub.2Cl.sub.2,
brought to acidic pH with Et.sub.2O/HCl and the solvent was removed
in vacuo. The resulting solid was triturated with Et.sub.2O,
filtered and dried, yielding 7.1 g of the title compound.
[0194] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0195] The following compounds were obtained according to
procedures described in Preparations 7-10:
[0196] 4-(3-Fluoro-2-methyl-phenyl)piperidine hydrochloride;
[0197] 4-(2-Chloro-phenyl)piperidine hydrochloride;
[0198] 4-Phenyl-piperidine hydrochloride;
[0199] 4-(2-Methyl-phenyl)-piperidine hydrochloride;
[0200] 4-(2-Fluoro-phenyl)-piperidine hydrochloride;
[0201] 4-(3-Methyl-phenyl)-piperidine hydrochloride;
[0202] 4-(2,5-Difluoro-phenyl)-piperidine hydrochloride;
[0203] 4-(2,6-Difluoro-phenyl)-piperidine hydrochloride;
[0204] 4-(2-Chloro-6-fluoro-phenyl)-piperidine hydrochloride;
[0205] 4-(2-Bromo-phenyl)-piperidine hydrochloride, and;
[0206] 4-(2-Trifluoromethyl-phenyl)-piperidine hydrochloride.
[0207] IR, .sup.1H nmr spectra and mass spectra for all the above
compounds were consistent with the assigned structures.
[0208] Preparation 11
[0209] 1-Benzyl-4-(3,5-dimethyl-phenyl)piperidin-4-ol
[0210] 5 mL (36.8 mmol) of 5-bromo-m-xylene were dissolved in 40 mL
of dry THF under a nitrogen atmosphere. The resulting solution was
cooled to -50.degree. C. and 36.5 mL (58.4 mmol) of a 1.6 M
solution of n-BuLi in hexane were added dropwise. The reaction
mixture was stirred 30 min, then a solution of 10.3 mL (58.4 mmol)
of 1-benzyl-4-piperidone in 20 mL of dry THF was added dropwise;
stirring was continued for 1 h at -50.degree. C., then the reaction
mixture was allowed to warm to room temperature overnight. Water
was added carefully and TIF was removed in vacuo; the resulting
aqueous solution was extracted with AcOEt, the organic phase was
dried and the solvent was removed in vacuo. The resulting crude
product was purified by flash chromatography, eluting with a
mixture CH.sub.2Cl.sub.2/MeOH/conc. NH.sub.4OH 100:2:0.4
respectively, yielding 5.44 g of the title compound.
[0211] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0212] Preparation 12
[0213]
1-Benzyl-4-(3-dimethyl-phenyl)-1,2,3,6-tetrahydropyridine
[0214] 5.44 g (18.41 mmol) of
1-benzyl-4-(3,5-dimethyl-phenyl)-piperidin-4- -ol were dissolved in
7 mL of glacial acetic acid, then a mixture of 3.3 mL of glacial
acetic acid and S mL of conc. H.sub.2SO.sub.4 was added dropwise,
keeping the temperature below 0.degree. C. The reaction mixture was
allowed to warm to room temperature and stirred 3 h, then it was
poured onto 20 g of crushed ice, carefully basified with conc. NaOH
solution and extracted with AcOEt. The organic phase was dried and
the solvent was removed in vacuo, yielding 4.4 g of the title
compound, which was used without further purification.
[0215] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0216] Preparation 13
[0217] 4-(3,5-Dimethylphenyl)piperidine
[0218] 1.24 g of 10% Pd on activated carbon were suspended in 15 mL
of water, then a solution of 4.4 g (15.86 mmol) of
1-benzyl-4-(3,5-diethylph- enyl)-1,2,3,6-tetrahydropyridine in 60
mL of EtOH was added followed by 1 mL of formic acid The resulting
mixture was hydrogenated at 45 p.s.i. in a Parr apparatus for 6 h,
then the catalyst was filtered off and the solvent was removed in
vacuo. The resulting residue was taken up in water, basified with
conc. NH.sub.4OH solution and extracted with CH.sub.2Cl.sub.2. The
organic phase was dried and the solvent was removed in vacuo,
yielding 2.5 g of the title compound, which was used without
further purification.
[0219] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0220] The following compound was obtained according to procedure
described in Preparation 13:
[0221] 4-(2,6-dimethyl-phenyl)-1,2,3,6-tetrahydropyridine.
[0222] IR, .sup.1H nmr spectra and mass spectra for the above
compound were consistent with the assigned structure.
[0223] Preparation 14
[0224] 4-(2,6-Dimethyl-phenyl)piperidine Hydrochloride
[0225] 250 mg (35.75 mmol) of lithium wires were added portionwise,
under an argon atmosphere at -78.degree. C., to 25 mL of liquid
ammonia, then 840 mg (4.47 mmol) of
4-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine dissolved in 15
mL of dry THF were added dropwise. The reaction mixture was stirred
1 h at -78.degree. C., then it was allowed to warm to room
temperature. After ammonia has been removed it was cooled to
0.degree. C. and 50 mL of water were added. The reaction mixture
was extracted with CH.sub.2Cl.sub.2, the organic layer was washed
with brine, dried and the solvent removed in vacuo. The resulting
oily residue was dissolved in CH.sub.2Cl.sub.2 and brought to
acidic pH with Et.sub.2O/HCl. The solvent was removed in vacuo and
the resulting solid was triturated with Ci-Pr)20, filtered and
dried, yielding 790 mg of the title compound.
[0226] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0227] Preparation 15
[0228] 4-(2-Hydroxymethyl-phenyl)-1-piperidinecarboxylic acid,
1,1-dimethylethyl Ester
[0229] 250 mg (0.87 mmol) of
4-(2-formyl-phenyl)-1,2,3,6-tetrahydropyridin- ecarboxylic acid
1,1-dimethylethyl ester (prepared as described in Wustrow,
Synthesis, 993, 1991) were dissolved in 35 mL of absolute EtOH. 125
mg of PtO.sub.2 were added and the resulting mixture was
hydrogenated in a Parr apparatus at 10 p.s.i. for 24 h, then the
catalyst was filtered off and the solvent was removed in vacuo,
yielding 260 mg of the title compound, which was used without
further purification.
[0230] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0231] Preparation 16
[0232] 4-(2-Hydroxymethyl-phenyl)piperidine hydrochloride
[0233] 260 mg (0.89 mmol) of
4-(2-hydroxymethylphenyl)-1-piperidinecarboxy- lic acid,
1,1-dimethylethyl ester were dissolved in 20 mL of
CH.sub.2Cl.sub.2, 4 mL of a saturated Et.sub.2O/HCl solution were
added and the reaction mixture was stirred at room temperature for
45 min. The solvent was removed in vacuo and the resulting crude
solid was triturated with CH.sub.2Cl.sub.2, filtered and dried,
yielding 180 mg of the title compound.
[0234] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0235] Preparation 17
[0236]
(.+-.)-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]6-
,7,8,9-tetrahydro-5H-benzocyclohepten-5-one
[0237] 1 g (4.58 mmol) of
(.+-.)-1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benz-
ocycloheptene-7-carboxylic acid was dissolved in 40 mL of dry
CH.sub.2Cl.sub.2 and 1.2 mL (13.74 mmol) of oxalyl chloride were
added dropwise at 0.degree. C. under a nitrogen atmosphere. The
solution was allowed to warm to room temperature overnight, then
the solvent and the excess oxalyl chloride were removed in vacuo.
The resulting acyl chloride was dissolved in 20 mL of dry
CH.sub.2Cl.sub.2 and added to a solution of 1.22 g (4.58 mmol) of
4-(2,6-dichloro-phenyl)-piperidine hydrochloride and 1.91 mL (13.74
mmol) of triethylamine in 30 mL of dry CH.sub.2Cl.sub.2 at
0.degree. C. The reaction mire was allowed to warm to room
temperature overnight, water was added, the organic phase was
collected, washed with 1 N HCl solution and dried. The solvent was
removed in vacuo and the resulting crude product was purified by
flash chromatography, eluting with a mixture Et2O/Hexane 8:2
respectively, yielding 1.4 g of the title compound.
[0238] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0239] The following compounds were obtained according to
procedures described in Preparation 17:
[0240]
(.+-.)-1-Fluoro-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-6,7,-
8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0241]
(.+-.)-1-Fluoro-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,-
8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0242]
(.+-.)-1-Methyl-7-[[42-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,-
9-tetrahydro-5H-benzocyclohepten-5-one;
[0243]
(.+-.)-1-Methyl-7-[[4-(3-methylphenyl)piperidin-1-ylcarbonyl]-6,7,8-
,9-tetrahydro-5H-benzocyclohepten-5-one;
[0244]
(.+-.)-1-Methyl-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-0.6,-
7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0245] (.+-.)
1-Bromo-7-[[4-(3-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8-
,9-tetrahydro-5H-benzocyclohepten-5-one;
[0246]
(.+-.)-1-Bromo-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-6,7,8-
,9-tetrahydro-5H-benzocyclohepten-5-one;
[0247]
(.+-.)-1-Methyl-7-[[4-(2,5-fluorophenyl)piperidin-1-yl]carbonyl]-6,-
7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0248]
(.+-.)-1-Methyl-7-[[s(2,6-fluorophenyl)piperidin-1-yl]carbonyl]-6,7-
,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0249]
(.+-.)-1-Methyl-7-[[4-(2-chlorosfluorophenyl)piperidin-1-yl]carbony-
l]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0250]
(.+-.)-1-Methyl-7-[[4-(2-bromophenyl)piperidin-1-yl]carbonyl]-6,7,8-
,9-tetrahydro-5H-benzocyclohepten-5-one;
[0251]
(.+-.)-1-Methyl-7-[[4-(2-trifluoromethylphenyl)piperidin-1-yl]carbo-
nyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0252]
(.+-.)-1-Methoxy-7-[(4phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrah-
ydro-5H-benzocyclohepten-5-one;
[0253]
(.+-.)-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]arbonyl]-6,7,-
8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0254]
(.+-.)-1-Methyl-7-[[4-(3-fluoro-2-methylphenyl)piperidin-1)-yl]carb-
onyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0255]
(.+-.)-1,4-Dimethyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]--
6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0256]
(.+-.)-1-Methyl-7-[[4-(2,6-dimethylphenyl)piperidin-1-ylcarbonyl]-6-
,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0257]
(.+-.)-1-Fluoro-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]--
6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0258]
(.+-.)-1-Fluoro-7-[(4,2,6-dimethylphenyl)piperidin-1-yl]carbonyl]-6-
,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0259]
(.+-.)-1,4-Diethyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbony-
l]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;
[0260]
(.+-.)-1-Methyl-7-[[4-(2,6-dimethylphenyl)piperidin-1-yl]carbonyl]--
6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one, and;
[0261]
(.+-.)-1-Methyl-7-[[4-(2-hydroxymethylphenyl)piperidin-1-yl]carbony-
l]-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-one.
[0262] IR, .sup.1H nmr spectra and mass spectra for all the above
compounds were consistent with the assigned structures.
[0263] Preparation 18
[0264]
(d)-1-Hydroxy-([4-(2-methylphenyl)piperidin-1-yilcarbonyl]-6,7,8,9--
tetrahydro-5H-benzocyclohepten-5-one
[0265] 780 mg (1.99 mmol) of
(.+-.)-1-methoxy-7-[[4-(2-methylphenyl)piperi-
din-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one
dissolved in 15 mL of CH.sub.2Cl.sub.2 were added dropwise, at room
temperature and under a nitrogen atmosphere, to a solution of 1.1
mL (11.94 mmol) of BBr.sub.3 in 10 mL of CH.sub.2Cl.sub.2. The
reaction mixture was stirred 2 h at room temperature, then it was
poured onto 20 g of crushed ice, basified with conc. NH.sub.4OH and
extracted with CH.sub.2Cl.sub.2. The organic layer was dried and
the solvent was removed in vacuo. The resulting crude solid was
triturated with Et.sub.2O, filtered and dried, yielding 600 mg of
the title compound.
[0266] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0267] Preparation 19
[0268]
(.+-.)-1-Trifluoromethanesulfonyloy-7-[[4-(2-methylphenylpiperidin--
1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one
[0269] 600 mg (1.59 mmol) of
(+1-hydroxy-7-[[4-(2-methylphenyl)piperdin-1--
yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were
dissolved in 5 mL of pyridine under a nitrogen atmosphere and 0.294
mL (1.75 mmol) of trifluoromethanesulfonic anhydride were added
dropwise at -5.degree. C. The reaction mixture was allowed to warm
to room temperature after 5 min and stirred overnight, then it was
poured in water, acidified with 20% citric acid solution and
extracted with AcOEt The organic layer was dried and the solvent
was removed in vacuo. The resulting residue was purified by flash
chromatography, eluting with
[0270] Et.sub.2O, yielding 520 mg of the title compound.
[0271] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0272] Preparation 20
[0273]
(.+-.)-1-Vinyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8-
,9-tetrahydro-5H-benzocyclohepten-5-one
[0274] 510 mg (1 mmol) of
(.+-.)-1-trifluoromethanesulfonyloxy-7-[[4-(2-me-
thylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-
-5-one were dissolved in 4 mL of DMF under an argon atmosphere,
then 72 mg (0.1 mmol) of dichlorobis(triphenylphosphine)palladium
(II), 340 mg (8 mmol) of LiCl and 105 mg (0.4 mmol) of
triphenylphosphine were added, followed by a solution of 0.3 mL
(1.04 mmol) of tributyl(vinyl)tin in 0.5 mL of DMF. The reaction
mixture was heated to 100.degree. C. for 6 h, then it was poured
into water and extracted with AcOEt. The organic layer was dried
and the solvent was removed in vacuo. The crude reaction mixture
was purified by flash chromatography, eluting with a mixture
AcOEt/hexane 1:1, yielding 90 mg of the title compound.
[0275] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0276] The following compound was obtained according to procedure
described in Preparation 20:
(.+-.)-1-Allyl-7-[[4-(2-methylphenyl)piperid-
in-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
[0277] IR, .sup.1H nmr spectra and mass spectra for the above
compound were consistent with the assigned structure.
[0278] Preparation 21
[0279]
(.+-.)-1-Ethyl-7-[[4-(2-methylphenylpiperidin-1-yl]carbonyl]-6,7,8,-
9-tetrahydro-5H-benzocyclohepten-5-ol
[0280] 100 mg of 10% Pd on activated carbon were suspended in 10 mL
of water, then a solution of 272 mg (0.7 mmol) of
(.+-.)-1-vinyl-7-[[4-(2-me-
thylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-
-5-one in 50 mL of EtOH was added, followed by 2 mL of formic acid.
The resulting mixture was hydrogenated at 45 p.s.i. in a Parr
apparatus for 7 h, then the catalyst was filtered off and the
solvent was removed in vacua. The resulting residue was taken up in
CH.sub.2Cl.sub.2 and extracted with water. The organic phase was
dried and the solvent was removed in vacuo, yielding 168 mg of the
title compound, which was used without further purification.
[0281] IR, .sup.1H nmr spectra and mass spectra were consistent
with the assigned structure.
[0282] Preparation 22.
[0283]
(.+-.)-1-Methoxy-7-[(phenylpiperidin-1-yl)methyl]-7,8,9-tetrahydro--
5H-benzocyclohepten-5one
[0284] 0.17 mL of the Jones reagent (prepared by mixing 2.67 g of
Cr and 2.3 mL of conc. H.sub.2SO.sub.4 and adding water up to a
final volume of 10 mL) were added to a solution of 0.2 g of
(.+-.)-1-methoxy-7-[(4phenylp-
iperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
in 13 mL of acetone. The solution was stirred at room temperature
for 1 h, then the solvent was removed in vacuo, the residue was
taken up in water, brought to basic pH with 10% NaOH and extracted
with CH.sub.2Cl.sub.2. The organic phase was dried and the solvent
was removed in vacuo, obtaining 0.15 g of the title compound, which
was used without further purification.
[0285] IR and .sup.1H nmr spectra were consistent with the assigned
structure.
EXAMPLE 1
[0286]
(.+-.)-cis-1-Methyl-7-[142-fluorophenyl)piperidin-1-yl]methyl]-6,7,-
8,9-tetrahydro-5H-benzocyclohepten-5-ol hydrochloride
[0287] 380 mg (1 mmol) of
(.+-.)-1-methyl-7-[[4-(2-fluorophenyl)piperidin--
1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one
dissolved in 5 mL of dry THF were added dropwise, at 0.degree. C.
and under a nitrogen atmosphere, to 5 mL of a 1 M solution of
LiAlH.sub.4 in TBF. The reaction mixture was allowed to warm to
room temperature and then heated to reflux for 3 h. After cooling
to 0.degree. C., the reaction mixture was quenched by sequential
addition of water, 15% NaOH solution and water. After stirring for
1 h, the resulting precipitate was filtered by suction and the
filtrate was evaporated to dryness. The resulting crude product was
purified by chromatography, eluting with a mixture
CH.sub.2Cl.sub.2/MeOH/conc. NH.sub.4OH 95:4:0.5 respectively,
yielding 60 mg of compound which was dissolved in Et.sub.2O and
brought to acidic pH with Et.sub.2O/HCl. The solvent was removed in
vacuo and the resulting solid was triturate with acetone, filtered
and dried, yielding 58 mg of the title compound.
m.p.=235-240.degree. C. IR (KBr, cm.sup.-1)=3435, 2927, 1492. NMR
(free base, 400 MHz, CDCl.sub.3, .delta. ppm): 7.43 (d, 1H);
7.29-6.97 (m, 6H); 5.04 (d, 1H); 3.13 (dd, 1H); 3.03-2.92 (m, 2H);
2.86 (m, 1H); 2.47 (dd, 1H); 2.33 (s, 3H); 2.24 (d, 1H); 2.17-2.00
(m, 6H); 1.85-1.74 (m, 5H); 1.31 (m, 1H); 0.88 (m, 1H). MS (m/z):
368 (MH+).
EXAMPLE 2
[0288]
(.+-.)-1-Methyl-7-[[4-(2-trifluoromethylphenyl)piperidin-1-yl]methy-
l]-6,7,8,9-tetrahydro 5H-benzocyclohepten-5-ol trifluoroacetate
[0289] The title compound was obtained according to the method
described in Example 1, but it was purified by flash chromatography
on Lichrosolv RP 18 stationary phase, by gradient elution with a
solvent system water/MeCN/TFA 900:100:0.5 respectively and
water/MeCN/TFA 100:900:0.5 respectively, in a 1:3 relative ratio,
yielding 20 mg of the title compound
[0290] NMR (free base, 400 Mz, CDCl.sub.3, .delta. ppm): 7.61 (d,
1H); 7.50 (m, 2H); 7.43 (d, 1H); 7.28 (m, 1H); 7.14 (dd, 1H); 7.07
(d, 1H); 5.04 (d, 1H); 3.14 (dd, 1H); 3.04-2.85 (m, 3H); 2.47 (dd,
1H); 2.33 (s, 3H): 2.30-2.00 (m, 7H); 1.89-1.71 (m, 5H); 1.34 (m,
1H); 0.89 (m, 1H). MS (m/z): 418 (MH+).
[0291] Compounds of formula (I) and described in Table 1 were
obtained following procedure described in Example I
1TABLE 1 Ex m.p. IR MS No. Name R R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 (.degree. C.) (cm.sup.-1) NMR (400 MHz, .delta. ppm, free
base) (m/z) 3 (.+-.)-cis-1-fluoro-7-[[4-(2- F H OH H 2-Cl H 245-
(KBr); CDCl.sub.3: 7.37-7.09(m, 6H); 6.92(t, 1H); 4.97(d, 1H): 388
chlorophenyl) 247 3262, 3.35(dd, 1H); 3.07-2.91(m, 3H);
2.39-2.21(m, 2H); (MH+) piperidin-1-yl]methyl]- 2932, 2.20-2.00(m,
6H); 1.88-1.65(m, 5H); 1.36(m, 1H); 6,7,8,9-tetrahydro-5H- 1579
0.93(m, 1H). benzocyclohepten-5-ol hydrochloride 4
(.+-.)-1-fluoro-7-[[4-(2- F H OH H 2-Me H 231- (KBr); CDCl.sub.3:
7.36(d, 1H); 7.28-7.06(m, 5H); 6.92(t, 1H); 367 methylphenyl) 233
3297, 4.97(d, 1H); 3.35(dd, 1H); 3.07-2.92(m, 2H); (M+.);
piperidin-1-yl]methyl]- 2927, 2.70(m, 1H); 2.38-2.23(m, 2H);
2.34(s, 3H); 2.20- 188; 6,7,8,9-tetrahydro-5H- 1582 1.99(m, 6H);
1.87-1.65(m, 5H); 1.37(m, 1H); 117; benzocyclohepten-5-ol 0.93(m,
1H). 70 hydrochloride 5 (.+-.)-cis-1-methyl-7-[[4- Me H OH H 3-Me H
>250 IR, 1H nmr spectra and mass spectra were consistent with
the assigned (3-methylphenyl) structure. piperidin-1-yl]methyl]-
6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride 6
(.+-.)-cis-1-methyl-7-[[4- Me H OH H 2-Cl H >250 (KBr);
CDCl.sub.3: 7.42(d, 1H); 7.34(dd, 1H); 7.29(dt, 1H); 383
(2-chlorophenyl) 3411, 7.23(dt, 1H); 7.16-7.09(m, 2H); 7.06(d, 1H);
(M+.); piperidin-1-yl]methyl]- 2925, 5.04(d, 1H); 3.14(dd, 1H);
3.07-2.93(m, 3H); 208 6,7,8,9-tetrahydro-5H- 1441 2.47(dd, 1H);
2.33(s, 3H); 2.24(d, 1H); benzocyclohepten-5-ol 2.19-2.02(m, 6H);
1.87-1.69(m, 5H); 1.31(m, 1H); hydrochloride 0.88(m, 1H). 7
(.+-.)-cis-1-methyl-7-[[4- Me H OH H 2-F 5-F -- -- CDCl.sub.3:
7.42(d, 1H); 7.14(dd, 1H); 7.06(d, 1H); 385 (2,5-difluorophenyl)
6.99-6.90(m, 2H); 6.87-6.79(m, 1H); 5.04(d, 1H); (M+.);
piperidin-1-yl]methyl]- 3.13(dd, 1H); 3.03-2.91(m, 2H);
2.88-2.77(m, 1H); 210 6,7,8,9-tetrahydro-5H- 2.46(dd, 1H); 2.32(s,
3H); 2.26-2.00(m, 7H); 1.81- benzocyclohepten-5-ol 1.68(m, 5H);
1.38-1.24(m, 1H); 0.87(m, 1H). hydrochloride 8
(.+-.)-cis-1-methyl-7-[[4- Me H OH H 2-F 6-F -- -- CDCl.sub.3:
7.43(d, 1H); 7.13(dd, 1H); 7.08(m, 1H); 385 (2,6-difluorophenyl)
7.06(d, 1H); 6.83(d, 1H); 6.80(d, 1H); 5.04(d, 1H); (M+.);
piperidin-1-yl]methyl]- 3.13(dd, 1H); 3.03-2.91(m, 3H); 2.46(dd,
1H); 210 6,7,8,9-tetrahydro-5H- 2.33(s, 3H); 2.29-1.97(m, 9H); 1.7
1-1.62(m, 3H); benzocyclohepten-5-ol 1.38-1.24(m, 1H); 0.87(m, 1H).
hydrochloride 9 (.+-.)-cis-1-vinyl-7-[[4-(2- Vinyl H OH H 2-Me H --
-- (CDCl.sub.3): 7.53(d, 1H); 7.32(d, 1H); 7.26-7.01(m, 376
methylphenyl) 6H); 5.52(dd, 1H); 5.30(dd, 1H); 5.05(d, 1H); (MH+)
piperidin-1-yl]methyl]- 4.80(s br, 1H); 3.24(dd, 1H); 2.98(m, 2H);
6,7,8,9-tetrahydro-5H- 2.69(m, 1H); 2.49(dd, 1H); 2.34(s, 3H);
benzocyclohepten-5-ol 2.28-1.93(m, 6H); 1.85-1.66(m, 5H); 1.33(m,
1H); hydrochloride 0.89(m, 1H). 10 (.+-.)-cis-1-allyl-7-[[4-(2-
Allyl H OH H 2-Me H -- -- (CDCl.sub.3): 7.48(d, 1H); 7.25(d, 1H);
7.21-7.04(m, 389 methylphenyl) 5H); 5.96(ddt, 1H); 5.03(m, 2H);
4.95(ddt, 1H); (M+.); piperidin-1-yl]methyl]- 3.43(m, 2H); 3.12(dd,
1H); 2.99(m, 2H); 2.69(m, 188; 6,7,8,9-tetrahydro-5H- 1H); 2.44(dd,
1H); 2.33(s, 3H); 2.24(d, 1H); 2.17- 117 benzocyclohepten-5-ol
1.99(m, 6H); 1.83-1.68(m, 5H); 1.34(m, 1H); hydrochloride 0.85(m,
1H). 11 (.+-.)-cis-1-methyl-7-[[4- Me H OH H 2-Me 3-F -- --
(CDCl.sub.3): 7.43(d, 1H); 7.16-7.02(m, 4H); 6.86(dd, 381
(3-fluoro-2- 1H); 5.04(d, 1H); 3.13(dd, 1H); 2.99(m, 2H); (M+.);
methylphenyl) 2.70(m, 1H); 2.46(dd, 1H); 2.33(s, 3H); 2.26- 206; 70
piperidin-1-yl]methyl]- 2.01(m, 7H); 2.23(d, 3H), 1.84-1.68(m, 5H);
6,7,8,9-tetrahydro-5H- 1.33(m, 1H); 0.88(m, 1H).
benzocyclohepten-5-ol hydrochloride 12 (.+-.)-trans-1-ethyl-7-[[4-
Et H OH H 2-Me H -- -- CDCl.sub.3: 7.25(d, 2H); 7.19-7.05(m, 5H);
5.03(m, 377 (2-methylphenyl) 1H); 3.13-2.87(m, 4H); 2.68(m, 3H),
2.33(s, 3H); (M+.); piperidin-1-yl]methyl]- 2.27-1.97(m, 8H);
1.87-1.69(m, 4H); 188 6,7,8,9-tetrahydro-5H- 1.52(m, 2H); 1.17(t,
3H). benzocyclohepten-5-ol hydrochloride 13
(.+-.)-trans-1,4-dimethyl- Me 4- OH H 2-Me H -- -- (CDCl.sub.3, 333
K): 7.25(d, 1H); 7.20-7.05(m, 3H); 378 7-[[4-(2-methylphenyl) Me
6.98(d, 1H); 6.91(d, 1H); 5.34(t. 1H); 3.20(m, 1H); (MH+)
piperidin-1-yl]methyl]- 3.00(m, 2H); 2.78(m, 1H); 2.69(m, 1H);
2.41(s, 6,7,8,9-tetrahydro-5H- 3H); 2.32(s, 3H); 2.28(s, 3H);
2.23-1.96(m, 6H); benzocyclohepten-5-ol 1.96-1.54(m, 7H); 1.02(m,
1H). 14 (.+-.)-cis-1-methyl-7-[[4- Me H OH H 2-Me 6- -- --
(CDCl.sub.3): 7.43(d, 1H); 7.14(dd, 1H); 7.06(d, 1H); 377
(2,6-dimethylphenyl) Me 6.98(s, 3H), 5, 11(s br, 1H); 5.03(d, 1H);
3.13(dd, (M+.); piperidin-1-yl]methyl]- 1H); 2.98(m, 3H); 2.46(dd,
1H); 242(s br, 6H); 202 6,7,8,9-tetrahydro-5H- 2.33(s, 3H); 2.25(m,
4H); 2.15-1.95(m, 6H); 1.39- benzocyclohepten-5-ol 1.15(m, 2H);
0.86(m, 1H). hydrochloride 15 (.+-.)-cis-1-fluoro-7-[[4- F H OH H
2-Me 6- -- -- (CDCl.sub.3): 7.36(d, 1H); 7.18(m, 1H); 6.97(s, 3H);
382 (2,6-dimethylphenyl) Me 6.92(dd, 1H); 4.97(d, 1H); 3.35(dd,
1H); 2.98(m, (MH+) piperidin-1-yl]methyl]- 3H); 2.42(s br, 6H);
2.40-1.97(m, 11H); 1.58(m, 6,7,8,9-tetrahydro-5H- 2H); 1.35 (m,
1H); 0.91(m, 1H). benzocyclohepten-5-ol hydrochloride 16
(.+-.)-1,4-dimethyl-7-[[4- Me 4- OH H 2-Me 6- -- -- (CDCl.sub.3):
6.97(d, 1H); 6.96(s, 3H); 6.92(d, 1H); 392 (2,6-dimethylphenyl) Me
Me 5.32(t, 1H); 3.19(m, 1H); 3.00-2.89(m, 3H); (MH+)
piperidin-1-yl]methyl]- 2.77(m, 1H); 2.42(s br, 9H); 2.42-2.19(m,
4H); 6,7,8,9-tetrahydro-5H- 2.28(s, 3H); 2.07(m, 2H); 1.89(m, 1H);
1.73(m, benzocyclohepten-5-ol 3H); 1.65-1.53(m, 4H). hydrochloride
17 (.+-.)-cis-1-methyl-7-[[4- Me H OH H 2- H -- -- (CDCl.sub.3):
7.38(d, 1H); 7.30(d, 1H); 7.24(d, 1H); 379 (2-hydroxymethyl
CH.sub.2OH 7.18(dd, 1H); 7.10(dd, 1H); 7.03(dd, 1H); 6.96(d, (M+.);
phenyl)piperidin-1- 1H); 4.92(d, 1H); 4.64(d, 2H); 3.09-2.83(m,
5H); 204; yl]methyl]-6,7,8,9- 2.76(m, 1H); 2.38(dd, 1H); 2.,23(s,
3H); 2.22- 167 tetrahydro-5H- 1.91(m, 7H); 1.80-1.61(m, 4H);
1.20(m, 1H); benzocyclohepten-5-ol 0.77(m, 1H).
EXAMPLE 18
[0292]
(.+-.)-cis-1-Methyl-7-[[(2chloro-6-fluorophenyl)piperidin-1-yl]meth-
yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol hydrochloride
[0293] 3.0 mL of a 1 M solution of diisobutylaluminium hydride in
hexane were added dropwise, at 0.degree. C. and under a nitrogen
atmosphere, to a solution of 350 mg (0.85 mmol) of
(.+-.)-1-methyl-7-[[4-(2-chloro-6-flu-
orophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten--
5-one in 6 mL of dry THF. The reaction mixture was allowed to warm
to room temperature overnight, then it was poured onto 20 mL of a
saturated solution of sodium potassium tartate tetrahydrate; 1 mL
of 15% NaOH solution was added and the aqueous phase was extracted
with Et.sub.2O. The organic phase was dried and the solvent was
removed in vacua. The crude product was purified by flash
chromatography, eluting with a mixture CH.sub.2Cl.sub.2/MeOFconc.
NH.sub.4OH 100:4:0.1 respectively, yielding 25 mg of compound which
was dissolved in Et.sub.2O and brought to acidic pH with
Et.sub.2O/HCl. The solvent was removed in vacuo and the resulting
solid was triturate with acetone, filtered and dried, yielding 15
mg of the title compound.
[0294] NMR (free base, 400 MHz, CDCl.sub.3, .delta. ppm): 7.43 (d,
1H); 7.16-7.04 (m, 4H); 6.93 (ddd, 1H); 5.03 (d, 1H); 3.20-3.10 (m,
2H): 3.02-2.92 (m, 2H); 2.46 (dd, 1H): 2.33 (s, 3H); 2.29-1.97 (m,
9H); 1.70-1.62 (m, 3H); 1.32 (m, 1H): 0.86 (m, 1H). MS (m/z): 401
(M+.); 226; 210.
EXAMPLE 19
[0295]
(.+-.)-1-Bromo-7-[[(2-chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-t-
etrahydro-5H-benzocyclohepten-5-ol Trifluoroacetate
[0296] The title compound was obtained according to the method
described in Example 18, but it was purified by preparative HPLC on
a Supelcosil ABZ+plus column, by gradient elution with a solvent
system water/MeCNITFA 900:100:0.5 respectively (A) and
water/MeCN/TFA 100:900:0.5 respectively (B), with a gradient from
0% B to 80% (B) in 19 min., yielding 14 mg of the title
compound.
[0297] NMR (free base, 400 MHz, CDCl.sub.3, .delta. ppm): 7.48 (dd,
1H); 7.367.18 (m, 4H); 7.12 (dd, 1H); 7.00 (dd, 1H); 5.03 (m, 1H);
3.35-3.13 (m, 1H); 3.05-2.93 (m, 2H); 2.262.02 (m, 8H); 1.87-1.70
(m, 6H); 1.58 (m, 1H); 1.26 (m, 1H). MS (m/z): 448 (MH+).
[0298] Compounds of formula (I) and described in Table 2 were
obtained following procedure described in Example 18
2TABLE 2 Ex m.p. IR MS No. Name R R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 (.degree. C.) (cm.sup.-1) NMR (400 MHz, .delta. ppm, free
base) (m/z) 20 (.+-.)-trans-1-bromo-7-[[4- Br H OH H 3-Me H >250
(KBr); CDCl.sub.3: 7.47(dd, 1H); 7.23(d, 1H), 7.17(d, 1H); 427
(3-methylphenyl) 3326, 7.05-6.97(m, 4H); 5.02(m, 1H); 3.33-3.14(m,
2H); (M+.); piperidin-1-yl]methyl]- 2959, 3.01-2.93(m, 2H);
2.49-2.38(m, 1H); 2.33(s, 3H); 188 6,7,8,9-tetrahydro-5H- 1446
2.25-1.92(m, 7H); 1.83-1.74(m, 5H); 1.54(m, benzocyclohepten-5-ol
1H); 1.22(m, 1H). hydrochloride 21 (.+-.)-cis-1-methyl-7-[[4-(2- -
Me H OH H 2-Br H -- -- CDCl.sub.3: 7.53(d, 1H); 7.42(d, 1H);
7.307.24(m, 2H); 428 bromophenyl) 7.13(dd, 1H); 7.06(d, 1H);
7.04(m, 1H); 5.04(d, (M+.); piperidin-1-yl]methyl]- 1H); 3.13(dd,
1H); 3.05-2.90(m, 3H); 2.47(dd, 1H); 252; 6,7,8,9-tetrahydro-5H-
3.33(s, 3H); 2.29-2.01(m, 8H); 1.88-1.64(m, 4H); 242;
benzocyclohepten-5-ol 1.34(m, 1H); 0.88(m, 1H).
EXAMPLE 22
[0299]
(.+-.)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl-
]6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol Hydrochloride
[0300] A solution of 1076 mg (8.06 mmol) of AlCl.sub.3 in 50 mL of
dry Et.sub.2O was added dropwise, at 0.degree. C. and under a
nitrogen atmosphere, to a suspension of 275 mg (7.25 mmol) of
LiAlH.sub.4 in 50 mL of dry Et.sub.2O. The resulting mixture was
stirred for 10 min., then 828 mg (1.92 mmol) of
(.+-.)-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-y-
l]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one dissolved
in 50 mL of dry Et.sub.2O were added dropwise. The reaction mixture
was allowed to warm to room temperature and stirred 4 h, then it
was cooled to 0.degree. C. and quenched with water, 15% NaOH
solution and water. The aqueous phase was extracted with Et.sub.2O,
the organic phase was dried and the solvent was removed in vacuo.
The crude product was purified by flash chromatography, eluting
with a mixture CH.sub.2Cl.sub.2/i-PrOH/conc- . NH.sub.4OH 100:2:0.1
respectively, yielding 200 mg offfie cis diastereoisomer as the
faster eluting compound 45 mg of free base were dissolved in
CH.sub.2Cl.sub.2, the solution was brought to acidic pH with
Et.sub.2O/HCl and the solvent was removed in vacuo. The resulting
solid was triturated with acetone, filtered and dried, yielding 40
mg of the title compound. m.p.=235-240.degree. C. IR (KBr,
cm.sup.-1)=3435, 2963, 1436, 1261, 1095. NMR (free base, 400 MHz,
CDCl.sub.3, .delta. ppm): 7.42 (d, 1H); 7.29-7.23 (m, 2H); 7.12
(dd, 1H); 7.05 (d, 1H); 7.01 (dd, 1H); 5.03 (d, 1H); 3.52 (tt, 1H);
3.16 (dd, 1H); 3.042.94 (m, 2H); 2.74-2.58 (m, 2H); 2.50 (dd, 1H);
2.34 (s, 3H); 2.27 (m, 1H); 2.19-2.03 (m, 6H); 1.59-1.40 (m, 31H);
1.32 (m, 1H); 0.90 (m, 1H). MS (m/z): 418 (MH+)
EXAMPLE 23
[0301]
(.+-.)-trans-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]meth-
yl]6,7,8,9-tetrahydro 5H-benzocyclohepten-5ol
[0302] The chromatography of the preceding example was continued,
obtaining 50 mg of the trans diastereoisomer as the slower eluting
compound.
[0303] NMR (400 MHz, CDCl, .delta. ppm): 7.30-7.25 (m, 2H);
7.147.00 (m,4H); 5.02 (m, 1H): 3.48 (tt, 1H); 3.11-2.87 (m, 4H);
2.71-2.55 (m, 2H); 2.34 (s, 31); 2.31-1.99 (m, 8H); 1.51 (m, 3H);
1.17 (m, 1H). MS (m/z): 418 (MH+).
[0304] Compounds of formula (I) and described in Table 3 were
obtained following procedure described in Example 22
3TABLE 3 Ex m.p. IR MS No. Name R R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 (.degree. C.) (cm.sup.-1) NMR (400 MHz, .delta. ppm, free
base) (m/z) 24 (.+-.)-cis-1-fluoro-7-[[4-(2,6- F H OH H 2-Cl 6-Cl
-- -- (CDCl.sub.3): 7.36(d, 1H); 7.27(m, 1H); 7.18(m, 1H); 422
dichlorophenyl) 7.04(d, 1H); 7.02(d, 1H); 6.92(dd, 1H); (MH+);
piperidin-1-yl]methyl]- 4.96(d, 1H); 3.49(tt 1H); 3.35(dd, 1H);
2.98(m, 6,7,8,9-tetrahydro-5H- 2H); 2.64(dq, 2H); 2.38-2.00(m, 9H);
1.54(m, benzocyclohepten-5-ol 2H); 1.35(m, 1H); 0.91(m, 1H).
hydrochloride 25 (.+-.)-1,4-dimethyl-7-[[4-(2,6- Me 4-Me OH H 2-Cl
6-Cl -- -- (CDCl.sub.3): 7.25(m, 2H); 7.02(dd, 1H); 6.98(d, 1H);
432 dichlorophenyl) 6.92(d, 1H); 5.33(dd, 1H); 3.47(tt, 1H);
3.18(dd, (MH+) piperidin-1-yl]methyl]- 1H); 2.96(m, 2H); 2.78(m,
1H); 2.64(m, 2H); 6,7,8,9-tetrahydro-5H- 2.42(s, 3H); 2.42-2.26(m,
4H); 2.28(s, 3H); benzocyclohepten-5-ol 2.17-2.00(m, 3H);
1.84-1.47(m, 5H).
[0305] Racemic
(.+-.)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-y-
l]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (compound of
Example 22) was separated by preparative HPLC on chiral stationary
phase (Daicel Chiralcel OD, elution with 95:5 Hexane:Ethanol, 17
mL/min), obtaining:
EXAMPLE 26
[0306]
(.+-.)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl-
]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
[0307] The title compound was obtained with e.e.>99.8% (HPLC).
[.alpha.].sup.20.sub.D=-30.7 (c=0.5, i-PrOH). .sup.1H NMR matched
that of the racemate.
EXAMPLE 27
[0308]
(.+-.)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl-
]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
[0309] The title compound was obtained with e.e.>99.8% (HPLC).
[a].sup.20.sub.D=+32.6 (c=0.5, i-PrOH).
[0310] .sup.1H NMR matched that of the racemate.
EXAMPLE 28
[0311]
(.+-.)-1-Methoxy-5methyl-7-[(4-phenylpiperidin-1-yl)methyl]6,7,8,9--
tetrahydro-5H-benzocyclohepten-5-ol hydrochloride
[0312] A solution of 140 mg (0.38 mmol) of
(.+-.)-1-methoxy-7-[(4phenylpip-
eridin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in
5 mL of dry Et.sub.2O was added, at 0.degree. C. and under a
nitrogen atmosphere, to 1 mL of a 3 M MeMgl solution in Et.sub.2O.
The reaction mixture was stirred 1 h at 0.degree. C., then allowed
to warm to room temperature and stirred an additional hour, then it
was cooled to 0.degree. C. and quenched with saturated NH.sub.4Cl
solution. The aqueous phase was extracted with Et.sub.2O, the
organic phase was collected, dried and the solvent was removed in
vacuo. The crude product was purified by flash chromatography,
eluting with a mixture toluene/MeOH 9:1 respectively, yielding 40
mg of free base, which was dissolved in Et.sub.2O, the solution was
brought to acidic pH with Et.sub.2O/HCl and the solvent was removed
in vacuo. The resulting solid was triturated with Et.sub.2O,
filtered and dried, yielding 30 mg of the title product
m.p.=158-160.degree. C.
[0313] .sup.1H nmr spectra was consistent with the assigned
structure.
[0314] Method of Nociceptin Binding Assay
[0315] Receptor Cloning and Expression
[0316] ORL-1 receptor was stably expressed in a Chinese Hamster
Ovary (CHO) cell line (ACC-317) using a pCDN vector. Subclone
selection was performed by growth in the absence of nucleosides.
The cell line expressing high numbers of ORL-1 binding sites was
selected for further characterization in radioligand binding and
signal transduction assay (cAMP and GTPgS assays).
[0317] Cell Growth Conditions
[0318] CHO cells are grown in suspension, in 1017 SO.sub.3 culture
and maintained at 37.degree. C. and 5% CO.sub.2. The cells are
routinely grown on a shaker in the presence of 0.05% (v/v) pluronic
acid (F68). The maximum cell density for this CHO cell lines is
4.times.106 cells/ml. The cultures are passed twice a week at a 1:5
or 1:10 dilution.
[0319] Membrane Preparation by Hypotonic Lysis
[0320] All steps are performed at 4.degree. C.
[0321] 1) Harvest cells in PBS (approximately 30.times.10.sup.6
cells/tube). Collect cells by centrifugation (1200 rpm, ca
800.times.g 5 min).
[0322] 2) Resuspend each pellet in 10 mM dibasic phosphate buffer,
pH 7.2 (buffer A)-circa 30 ml/pellet. Centrifuge 15000 rpm 10 min
(Sorvall SS-34 rotor).
[0323] 3) Resuspend the pellets in the same volume of buffer A,
incubate on ice for 20 min. Centrifuge at 1200 rpm, 5 min and save
the supernatants.
[0324] 4) Resuspend the low speed pellets in buffer A again and
repeat step 3) two more times saving the supernatants each
time.
[0325] 5) Pool the low speed supernatants. Spin (15000 rpm, 10 min)
to collect the membranes.
[0326] 6) Resuspend the pellets in buffer A containing 0.32 M
sucrose and S mM EDTA (buffer B). Pool, spin again at high speed to
concentrate the membranes and wash in this storage buffer.
[0327] 7) Resuspend in buffer B the final pellet to a final
concentration of 5-10 mg protein/ml (ca 10.times.10.sup.6
cells/ml). Freeze the aliquots at -80.degree. C.
[0328] Radioligand Binding
[0329] Radioligand binding experiments have been performed in Tris
buffer pH 7.4 containing 100 ug/ml Bacitracine, 4 ug/ml Leupeptine
and 2 ug/ml Chymostatine at the final volume of 1 ml, using
[.sup.3H]-Nociceptin (Amersham, 172 Ci/mmol) as the
radioligand.
[0330] Binding experiments were carried out at 25.degree. C. for 20
min and the reaction was terminated by filtration through Whatman
GF/B filters pretreated with 0.2% PEI. Filters were washed 3 times
in Tris buffer pH 7.4 at 4.degree. C. The radioactivity present on
the discs was measured by liquid scintillation counting using a
2500 Canberra Packard beta counter.
[0331] The most potent compounds in accordance with the present
invention have an ORL-1 binding affinity (Ki) in the range from 0.1
to 500 nNM.
* * * * *